Eosinophilic inflammation of the airways plays a central role in the pathogenesis of asthma. The frequency of asthma exacerbations appears to be closely related to airway inflammation [FitzGerald, 2006]. Eosinophilic inflammation is promoted by T-helper 2 (Th2) cytokines. Mepolizumab (Nucala) binds with high specificity and affinity to human interleukin 5 (IL-5), the key Th2 cytokine responsible for regulation of blood and tissue eosinophils. The overproduction of IL-5 has been specifically reported in patients with a variety of eosinophil associated disorders including asthma. Mepolizumab (Nucala) prevents IL-5 from binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface and thus inhibits IL-5 signaling and the overexpression of peripheral blood and tissue eosinophils. By neutralizing IL-5 and reducing eosinophilic inflammation in the lung, mepolizumab (Nucala) reduces exacerbations and improves asthma control.

Mepolizumab (Nucala) should be reconstituted and administered by a healthcare professional. In line with clinical practice, monitoring of patients after administration of biologic agents is recommended. Reconstitution Instructions Reconstitute Mepolizumab in the vial with 1.2 mL Sterile Water for Injection, USP, preferably using a 2- or 3-mL syringe and a 21-G needle. The reconstituted solution will contain a concentration of 100 mg/mL mepolizumab (Nucala). Do not mix with other medications.

The asthma development program for Mepolizumab (Nucala) included 3 double-blind, randomized, placebo-controlled trials: 1 dose-ranging and exacerbation trial (Trial 1) and 2 confirmatory trials (Trials 2 and 3). Mepolizumab (Nucala) was administered every 4 weeks in all 3 trials as add-on to background treatment. All subjects continued their background asthma therapy throughout the duration of the trials.

Trial 1 was a 52-week dose-ranging and exacerbation-reduction trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects enrolled in this trial were required to have at least 1 of the following 4 pre-specified criteria in the previous 12 months: blood eosinophil count greater than or equal to 300 cells/mcL, sputum eosinophil count greater than or equal to 3%, exhaled nitric oxide concentration greater than or equal to 50 ppb, or deterioration of asthma control after less than or equal to 25% reduction in regular maintenance inhaled corticosteroids/oral corticosteroids. Three IV doses of mepolizumab (75, 250, and 750 mg) administered once every 4 weeks were evaluated compared with placebo. Results from this trial and the pharmacodynamic study supported the evaluation of mepolizumab 75 mg IV and 100 mg SC in the subsequent trials. Mepolizumab (Nucala) is not indicated for IV use and should only be administered by the SC route.

A total of 711 subjects with asthma were studied in the 2 confirmatory trials (Trials 2 and 3). In these 2 trials subjects were required to have blood eosinophils of greater than or equal to 150 cells/mcL at screening (within 6 weeks of dosing) or blood eosinophils of greater than or equal to 300 cells/mcL within 12 months of enrollment. The screening blood eosinophils of greater than or equal to 150 cells/mcL criterion was derived from exploratory analyses of data from Trial 1. Trial 2 was a 32-week placebo- and active-controlled trial in subjects with asthma with a history of 2 or more exacerbations in the previous year despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) with or without oral corticosteroids. Subjects received mepolizumab (Nucala) 75 mg IV (n = 191), mepolizumab (Nucala) (n = 194), or placebo (n = 191) once every 4 weeks for 32 weeks. Trial 3 was a 24-week oral corticosteroid-reduction trial in subjects with asthma who required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control. Subjects in Trial 3 were not required to have a history of exacerbations in the prior year. Subjects received mepolizumab (Nucala) (n = 69) or placebo (n = 66) once every 4 weeks for 24 weeks. The baseline mean oral corticosteroid use was similar in the 2 treatment groups: 13.2 mg in the placebo group and 12.4 mg in the group receiving mepolizumab.

Reslizumab (Cinqair) is an interleukin-5 antagonist monoclonal antibody (IgG4, kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype. FDA approval was granted in March of 2016. Reslizumab (Cinqair) is not indicated for the treatment of other eosinophilic conditions, or for the relief of acute bronchospasm or status asthmaticus.

Reslizumab should is administered by intravenous infusion only by a healthcare professional, and should not be given by IV push or bolus. During and after administration the patient should be monitored for severe systemic reactions including anaphylaxis.

There were a total of 4 double-blind, placebo-controlled, clinical trials (studies I-IV) 16-52 weeks in duration involving 981 patients 12 years of age and older. While patients aged 12-17 years were included in these trials, reslizumab (Cinqair)is not approved for use in this age group. All subjects continued their background asthma therapy throughout the duration of the studies.

Studies I and II were 52-week studies in 952 patients with asthma who were required to have a blood eosinophil count of at least 400 cells/mcL within 3-4 weeks of dosing, and at least 1 asthma exacerbation requiring systemic corticosteroid use over the past 12 months. The majority of patients (82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to 10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients were on OCS at baseline. Reslizumab (Cinqair) 3mg/kg administered once every 4 weeks for a total of 13 doses was evaluated compared with placebo. In studies I and II, patients receiving reslizumab (Cinqair) 3mg/kg administered once every 4 weeks had significant reductions in the rate of all asthma exacerbations compared to placebo with a rate of 0.90 for reslizumab and 1.80 with placebo in study I (RR 0.5, 95% CI 0.37-0.67). In study II the rate of asthma exacerbations was 0.86 on reslizumab (Cinqair) versus 2.11 on placebo (RR 0.41, 95% CI 0.28-0.59). The study did not show a statistically significant benefit with regard to hospitalizations due to asthma exacerbations. Changes in FEV₁ at 16 weeks for both studies I and II were 137mL (76, 198), and 93mL (30, 155), respectfully.

Study III was a 16-week study in 315 patients who were required to have a blood eosinophil count of at least 400/mcL at screening (within 3 to 4 weeks of dosing). Maintenance oral corticosteroids were not allowed. Reslizumab (Cinqair) 3 mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. While 2 doses of reslizumab (Cinqair) were studied, reslizumab (Cinqair) 3 mg/kg is the only recommended dose. Change in FEV₁ over 16 weeks in study III was 160mL (60, 259).

Study IV was a 16-week study in 496 patients unselected for baseline blood eosinophil levels (approximately 80% of patients had a screening [within 3 to 4 weeks of dosing] blood eosinophil count of less than 400/mcL). Maintenance OCS were not allowed. Reslizumab (Cinqair) 3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. Change in FEV₁ over 16 weeks when compared to placebo was 76mL (-6, 158). An association of treatment effect (the difference between reslizumab (Cinqair) and placebo in the change in FEV₁ at week 16) and baseline blood eosinophils was not observed.

Benralizumab (Fasenra) is an interleukin-5-receptor alpha-directed cytolytic monocloncal antibody (IgG1, kappa) indicated for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. FDA approval was granted in November of 2017. Benralizumab (Fasenra) is not indicated for the treatment of other eosinophilic conditions or for the relief of acute bronchospasm or status asthmaticus.

Benralizumab (Fasenra) comes in a 30mg/mL single-dose prefilled syringe and should be administered by a healthcare professional as a subcutaneous injection. The asthma development program for benralizumab (Fasenra) included one 52-week dose-ranging exacerbation trial, three confirmatory trials (trial 1, trial 2, trial 3), and one 12-week lung function trial. A long term safety extension of the 3 confirmatory trials is currently ongoing.

The dose-ranging trial was a phase 2 randomized, double-blind, placebo controlled, 52-week trial which enrolled 609 asthmatic patients ages 18 or older. Patients were treated with benralizumab (Fasenra) 2mg, 20mg, or 100mg or placebo administered subcutaneously every 4 weeks for 3 doses followed by every 8 weeks. Patients were required to have a history of 2 or more asthma exacerbations (but no more than 6) requiring systemic corticosteroid treatment in the past 12 months, ACQ-6 score of 1.5 at least twice during screening, and reduced morning lung function at screening despite treatment with medium- or high-dose inhaled corticosteroid (ICS) plus long-acting beta₂ agonist (LABA). Patients were stratified by eosinophilic status. Results from this trial and exposure-response modelling of exacerbation rate reduction supported the evaluation of 30mg SC in the subsequent trials. Benralizumab (Fasenra) is not approved at 2mg, 20mg, or 100mg doses, and should only be administered at the recommended dose of 30mg.

Trials 1 and 2 (two of the confirmatory trials) were phase III, randomized, double-blind, parallel-group, placebo-controlled, exacerbation trials in patients 12 years and older and were 48 and 56 weeks, respectively. The trials randomized a total of 2510 patients who were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months, ACQ-6 score of 1.5 or more at screening and reduced lung function at baseline (pre-bronchodilator FEV₁ below 80% in adults and below 90% in adolescents) despite regular treatment with high-dose ICS (trial 1) of with medium or high-dose ICS (trial 2) plus a LABA with or without oral corticosteroids and additional asthma controller medications. Patients were stratified by geography, age, and blood eosinophil count (>300 cells/mcL or <300 cells/mcL). In both studies, patients were randomized to receive benralizumab (Fasenra) 30mg SC once every 4 weeks for the first 3 doses then every 4 weeks, Benralizumab(Fasenra) 30mg SC once every 4 weeks for the first 3 doses then every 8 weeks, or placebo SC every 4 weeks. All subjects continued their background asthma therapy throughout the duration of the trials. In both studies the percentage of patients who experienced adverse events was similar in the benralizumab and placebo groups. The most common events in patients treated with benralizumab were worsening asthma and nasopharyngitis.

The primary endpoint for trials 1 and 2 was the rate of asthma exacerbation in patients with baseline blood eosinophil counts greater than or equal to 300 cells/mcL who were taking high-dose ICS and LABA. In trial 1, 35% of patients receiving benralizumab (Fasenra) experienced an asthma exacerbation compared to 51% on placebo. In trial 2, 40% receiving benralizumab (Fasenra) experienced and asthma exacerbation compared to 51% on placebo. In both trials, patients with a baseline blood eosinophil count greater than or equal to 300 cells/mcL and a history of 3 or more exacerbations within 12 months showed a numerically greater exacerbation response.

Trial 3 was a phase III randomized, double-blind, parallel-group, 28-week, oral corticosteroid (OCS) reduction trial in 220 asthma patients. Patients were required to be 18 to 75 years of age with physician-diagnosed asthma requiring treatment with daily OCS (7.5mg to 40mg per day) in addition to regular use of high-dose ICS and LABA with or without additional controller(s) for at least 12 months prior to enrollment. The trial included an 8-week run-in period during which the OCS was titrated to the minimum effective dose without losing asthma control. Asthma control was based on a patient’s FEV₁, peak expiratory flow, nighttime awakenings, short-acting bronchodilator rescue medication or any other symptom that would require an increase in OCS dose. Patients were required to have blood eosinophil counts greater than or equal to 150 cells/mcL and a history of at least 1 exacerbation in the past 12 months. There were 3 treatment groups (placebo, benralizumab (Fasenra) every 4 weeks, and benralizumab (Fasenra) every 4 weeks for the first 3 doses and then once every 8 weeks). While 2 dosing regimens were studied in trial 1, 2, and 3, the recommended dose is 30mg benralizumab (Fasenra)administered every 4 weeks for the first 3 doses, then every 8 weeks thereafter.

The median percent reduction in daily OCS dose from baseline was 75% in patients receiving benralizumab (Fasenra) (95% CI: 60, 88) compared to 25% in patients receiving placebo (95% CI: 0, 33). The frequency of adverse events was similar between both groups and the most frequently reported events were nasopharyngitis, worsening asthma, and bronchitis. Two patients in the benralizumab (Fasenra) group died during treatment; 1 death due to acute cardiac failure was deemed unrelated to benralizumab (Fasenra), and the other was due to pneumonia which was deemed related to benralizumab (Fasenra).

The 12-week lung function trial was conducted in 211 patients with mild to moderate asthma. Patients were treated with placebo or benralizumab 30mg SC every 4 weeks for 3 doses. Lung function was improved in benralizumb (Fasenra) group compared to placebo.

In December 2017, mepolizumab (Nucala) was approved for the treatment of eosinophilic granulomatosis with polyangiitis (EPGA). The approval was based on a multicenter, double-blind, parallel group, phase 3 trial where patients with relapsing or refractory EPGA who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab (Nucala) or placebo, plus standard of care, for 52 weeks. The primary end points were accrued weeks of reemission and the proportion of participants in remission at week 36 and week 48. Inclusion criteria included previous treatment and EPGA. EPGA was defined as a history or presence of asthma, a blood eosinophil level of 10% or an absolute eosinophil count of more than 1000 cell per cubic meter, and the presence of two or more criteria that are typical of EPGA. Mepolizumab (Nucala) resulted in more accrued weeks of remission than placebo (28% vs 3% had > 24 weeks of accrued remission, P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%, P<0.001). A total of 3 patients in the mepolizumab (Nucala) group and 7 patients in the placebo group discontinued treatment.

In June 2019, FDA approved two new methods for administering mepolizumab (Nucala), an autoinjector and a pre-filled safety syringe, for patients or caregivers to administer once every four weeks, after a healthcare professional decides it is appropriate. This is the first anti-IL5 biologic to be licensed in the US for at-home administration, and the first respiratory biologic to be approved for administration via an autoinjector. In terms of the self-administration forms, mepolizumab (Nucala) is available as a 100mg/ml autoinjector solution for injection and a 100mg/ml prefilled syringe solution for injection.

In September 2019, FDA approved mepolizumab (Nucala) for use in children 6–11 years of age with severe eosinophilic asthma. The FDA approval is supported by an open-label study, conducted in children aged 6 to 11 years and suffering from severe eosinophilic asthma that investigated mepolizumab (Nucala)’s pharmacokinetics, pharmacodynamics and long-term safety. Evidence from adequate and well-controlled trials in adults and adolescents also supported approval in this age group. The 52-week long-term phase of the study showed that the safety profile in pediatric patients aged 6 to 11 years was similar to the known safety profile in patients aged 12 years and older.

In October 2019, FDA approved benralizumab (Fasenra) for self-administration in a 30mg/ml prefilled, single-use autoinjector called the FASENRA Pen.

The FDA approved package inserts for mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra) include the following warnings and precautions:

• Hypersensitivity reactions (eg, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred following administration of these agents. These reactions generally occur within hours of administration but in some instances can have a delayed onset (i.e. days). In the event of a hypersensitivity reaction, the agent should be discontinued.
• Acute Asthma Symptoms or Deteriorating Disease – these agents should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.
• Reduction of Corticosteroid Dosage - Do not discontinue systemic or inhaled corticosteroids (ICS) abruptly upon initiation of therapy with these agents. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
• Parasitic (Helminth) Infection - It is unknown if these agents will influence a patient’s response against parasites. Treat patients with pre-existing helminth infections before initiating therapy. If patients become infected while receiving treatment with these agents and do not respond to anti-helminth treatment, discontinue treatment with the agent until infection resolve.

The requirements of the Horizon BCBSNJ Monoclonal Interleukin-5 Antagonists [mepolizumab (Nucala), reslizumab (Cinqair) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Please refer to a separate policy on Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) under the Drug Section.

A. The add-on maintenance treatment of severe persistent asthma (see Appendix B) when ALL of the following criteria are met:

i. Age ≥ 6 years (Nucala), age ≥ 12 years (Fasenra) or ≥ 18 years (Cinqair)

ii. Evidence of reversibility; (This requirement is necessary to document that the condition being treated is asthma and not a restrictive or other chronic lung disease. Ideally, there should be demonstration of at least a >12% improvement in FEV₁ or >20% improvement in PEF after using a short acting inhaled beta-2 agonist).

iii. Member is symptomatic (or inadequately controlled) despite continued regular use of medium- to high-dose inhaled corticosteroids and an additional controller medication (e.g. long-acting beta agonist, etc.) consistent with Global Initiative for Asthma (GINA) 2019 guidelines (see step 5 in Appendix A).

iv. Member has at least 2 or more exacerbations in the previous year requiring daily oral corticosteroids (for at least 3 days in addition to the regular maintenance therapy)

v. Evidence to support eosinophilic airway disease by the following:


1. For Nucala: An elevated peripheral blood eosinophil level of ≥150 cells/µL at baseline (within 6 weeks of initial dosing) OR an elevated peripheral blood eosinophil level of ≥300 cells/µL in the prior 12 months

2. For Cinqair: An elevated peripheral blood eosinophil level of ≥400 cells/µL at baseline (within 3-4 weeks of initial dosing)

3. For Fasenra: An elevated peripheral blood eosinophil level of ≥150 cells/µL at baseline

[INFORMATIONAL NOTE: For Fasenra, there was no inclusion criteria requirement for baseline eosinophil level for two of the confirmatory trials while the third trial did have an inclusion criteria of eosinophil level of ≥150 cells/µL at baseline. In the two confirmatory trials without a level requirement, patients were stratified by baseline blood eosinophil counts of ≥300 cells/µL and <300 cells/µL and were randomized according to an approximate 2:1 allocation ratio. Reductions in exacerbation rates were observed irrespective of baseline peripheral eosinophil counts; however, patients with a baseline blood eosinophil count ≥300 cells/µL showed a numerically greater response than those with counts of <300 cells/µL. Nominally significant reductions were seen in the 300-448 cells/µL (31%, p=0.0178) and ≥450 cells/µL (50%, p<0.0001) categories.]


vi. Member is not currently being treated with omalizumab or another parenteral IL-5 antagonist

vii. Baseline information of patients clinical status; including forced expiratory volume and number of asthma exacerbations in past six months, corticosteroid use in past six months, rescue medication use in past six months, and number of hospitalizations or emergency room visits in the past six months

viii. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis

ix. If a subcutaneous form of the drug is requested, the requested drug will be administered in an office/outpatient setting by a healthcare professional or home infusion by a home-health nurse and is there is documentation that member will not be self-administering. Documentation must be provided stating the member is unable to self-administer due to one of the following reasons:
· Member has a history of anaphylaxis to prior therapy with a related pharmacologic or biologic agent despite standard premedication; or
· Member is unable to successfully self-administer with proper technique due to a motor/dexterity condition; or
· Member has acute mental status/cognitive changes or physical impairment due to another condition; or
· Member has in the past demonstrated compliance issues and therefore needs medical supervision to adequately receive the drug; or
· Member has clinically diagnosed needle phobia (supported by documentation including a psychiatric evaluation) and therefore cannot self-administer; or
· Member’s age prohibits them to successfully administer the medication and their medications cannot adequately be managed by a caregiver

[INFORMATIONAL NOTE: Combination treatment with mepolizumab and omalizumab has not been studied. Two post-hoc analyses conducted of the MENSA and SIRIUS trials found that treatment with mepolizumab resulted in a significant reduction in exacerbations, relative to placebo, irrespective of patients’ history of treatment with omalizumab. Likewise, there are no studies for the combination use of reslizumab and omalizumab.

During clinical trials for reslizumab, 496 patients who were previously unselected due to baseline blood eosinophil levels of <400 cells/µL were enrolled in study IV. There was no statistically significant benefit in any subgroup with an eosinophil level of <400 cells/µL]

B. The treatment with mepolizumab (Nucala only) for adult patients with eosinophilic granulomatosis with polyangiitis (EPGA) when ALL of the following criteria is met:

i. ≥18 years of age
ii. Diagnosis of eosinophilic granulomatosis with polyangiitis based on the following
a. History or presence of asthma
b. Blood eosinophil level of greater than 10% OR an absolute eosinophil count of more than 1000 cells per cubic millimeter
c. Presence of two or more criteria that are typical of EPGA including:
i. Histopathological evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, eosinophil-rich granulomatous inflammation
ii. Neuropathy
iii. Pulmonary infiltrates
iv. Sino-nasal abnormality
v. Cardiomyopathy
vi. Glomerulonephritis
vii. Alveolar hemorrhage
viii. Palpable purpura
ixi. Antineutrophil cytoplasmic antibody positivity
d. Member has been on stable doses of concomitant oral corticosteroid therapy for at least 4 weeks (i.e., prednisone or prednisolone at a dose of 7.5 mg/day)
e. Baseline Birmingham Vasculitis Activity Score (BVAS)
iii. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis
iv. The requested drug will be administered in an office/outpatient setting by a healthcare professional or home infusion by a home-health nurse and is there is documentation that member will not be self-administering. Documentation must be provided stating the member is unable to self-administer due to one of the following reasons:
· Member has a history of anaphylaxis to prior therapy with a related pharmacologic or biologic agent despite standard premedication; or
· Member is unable to successfully self-administer with proper technique due to a motor/dexterity condition; or
· Member has acute mental status/cognitive changes or physical impairment due to another condition; or
· Member has in the past demonstrated compliance issues and therefore needs medical supervision to adequately receive the drug; or
· Member has clinically diagnosed needle phobia (supported by documentation including a psychiatric evaluation) and therefore cannot self-administer; or
· Member’s age prohibits them to successfully administer the medication and their medications cannot adequately be managed by a caregiver

[INFORMATIONAL NOTE: Birmingham Vasculitis Activity Score (BVAS) scoring criteria can be found at the following link: https://www.canvasc.ca/pdf/bvasv3.pdf

The Birmingham Vasculitis Activity Score (BVAS) is as follows:

i. General:

· Myalgia
· Arthralgia
· Fever > 38 C
· Weight loss >22
ii. Cutaneous
· Infarct
· Purpura
· Gangrene
· Other Skin conditions
iii. Mucous membranes / eyes
· Mouth uclers
· Genital ulcers
· Adnexal inflammation
· Significant proptosis
· Scleritis/ Episcleritis
· Conjunvtivitis / Blepharitis / Keratitis
· Blurred vision
· Uveitis
· Retinal changes (vasculitis / thrombosis / exudate / haemorrhage)
iv. Ear Nose Throat (ENT)
· Bloody nasal discharge / crusts / ulcers / granulomata
· Paranasal sinus involvement
· Subglottic stenosis
· Conductive hearing loss
· Sensorineural hearing loss
v. Chest
· Wheeze
· Nodules or cavities
· Pleural effusion / pleurisy
· Infiltrate
· Endobronchial involvement
· Massive haemoptysis / alveolar haemorrhage
· Respiratory failure
vi. Cardiovascular
· Loss of pulses
· Valvular heart disease
· Pericarditis
· Ischaemic cardiac pain
· Cardiomyopathy
· Congestive cardiac failure
vii. Abdominal
· Peritonitis
· Bloody diarrhoea
· Ischaemic abdominal pain
viii. Renal
· Hypertension
· Proteinuria >1+
· Haematuria ≥10 RBCs/hpf
· Creatinine 125-249μ/L(1.41-2.82mg/dl) [Can only be scored on the first assessment]
· Creatinine 250-499 μ/L(2.83-5.64mg/dl) [Can only be scored on the first assessment]
· Creatinine ≥500 μ/L (≥5.66mg/dl) [Can only be scored on the first assessment]
· Rise in serum creatinine >30% or fall in creatinine clearance >25%
ix. Nervous System
· Headache
· Meningitis
· Organic confusion
· Seizures (not hypertensive)
· Stroke
· Spinal cord lesion
· Cranial nerve palsy
· Sensory peripheral neuropathy
· Mononeuritis multiplex ]

For the add on maintenance treatment of severe persistent asthma:
A. Nucala: 100mg administered subcutaneously once every 4 weeks for members 12 years and older OR 40mg administered subcutaneously once every 4 weeks for members 6 to 11 years
B. Cinqair: 3mg/kg administered intravenously over 20-50 minutes once every 4 weeks
C. Fasenra: 30mg administered subcutaneously once every 4 weeks for the first 3 doses, followed by once every 8 weeks thereafter

For the treatment of EPGA:
A. Nucala: 300 mg administered once every 4 weeks by subcutaneous injection as 3 separate 100-mg injections

• The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis
• If a subcutaneous form of the drug is requested, the requested drug will be administered in an office/outpatient setting by a healthcare professional or home infusion by a home-health nurse and is there is documentation that member will not be self-administering. Documentation must be provided stating the member is unable to self-administer due to one of the following reasons:
  · Member has a history of anaphylaxis to prior therapy with a related pharmacologic or biologic agent despite standard premedication; or
  · Member is unable to successfully self-administer with proper technique due to a motor/dexterity condition; or
  · Member has acute mental status/cognitive changes or physical impairment due to another condition; or
  · Member has in the past demonstrated compliance issues and therefore needs medical supervision to adequately receive the drug; or
  · Member has clinically diagnosed needle phobia (supported by documentation including a psychiatric evaluation) and therefore cannot self-administer; or
  · Member’s age prohibits them to successfully administer the medication and their medications cannot adequately be managed by a caregiver
• There are no unacceptable toxicities (e.g. hypersensitivity reactions including anaphylaxis, angioedema, urticaria, rash, malignancy, parasitic infection, herpes zoster infection)
• There is documented evidence of efficacy as evidenced by:
  • Continuation for the treatment of severe or persistent asthma
    • reduced number of asthma exacerbations; OR
    • reduced systemic corticosteroid usage; OR
    • two-fold or greater decrease in inhaled corticosteroid use for at least 3 days; OR
    • reduced utilization of rescued medications; OR
    • improvements in pulmonary function tests; OR
    • reduced number of hospitalizations, emergency room visits, or unscheduled visits to healthcare provider; OR
    • reduced reported asthma symptoms; OR
    • improvement from baseline in forced expiratory volume in 1 second (FEV₁)
  • Continuation for the treatment of EPGA
    · Reduced BVAS score compared to baseline OR
    · Reduced corticosteroid usage OR
    · Reduced asthma symptoms OR
    · Reduction number of hospitailizations or emergency room visits OR
    · Improvement from baseline in forced expiratory volume in 1 second (FEV₁) OR
    · Improvement in duration of remission or decrease in the rate of relapses OR
    · Patient is in remission [defined as a Birmingham Vasculitis Activity Score (BVAS) score=0 and a prednisone/prednisolone daily dose of ≤ 7.5mg]
    

Questions	Score:
1. On average, during the past week, how often were you woken by your asthma during the night?	0: Never 1:Hardly ever 2:A few times 3:Sevearl tines 4: Many times 5: A great many times 6: Unable to sleep because of asthma
2. On average, during the past week, how bad were your asthma symptoms when you woke up in the morning?	0: No symptoms 1: Very mild symptoms 2: Mild symptoms 3: Moderate Symptoms 4: Quite severe symptoms 5: Severe symptoms 6: Very severe symptoms
3. In general, during the past week, how limited were you in your activities because of your asthma?	0: Not limited at all 1: Very slightly limited 2: Slightly limited 3: Moderately limited 4: Very limited 5:Extemely limited 6: Total limited
4. In general, during the past week, how much shortness of breath did you experience because of your asthma?	0: None 1: A very little 2: A little 3: A moderate amount 4: Quite a lot 5: A great deal 6: A very great deal
5. In general, during the past week, how much of the time did you wheeze?	0: Not at all 1: Hardly any of the time 2: A little of the time 3: A moderate amount of time 4: A lot of the time 5: Most of the time 6: All of the time
6. FEV1	0: > 95% 1: 95%-90% 2:89%-80% 3:79% -70% 4:69% - 60% 5:59% - 50% 6:< 50%

5. Mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra)are considered investigational for all other indications.

APPENDIX A: Stepwise Approach for Managing Asthma

Step 1: As-needed SABA with no controller: this is indicated only if symptoms are rare, there is no night waking due to asthma, no exacerbations in the last year, and normal FEV1. Other options: regular low dose ICS to reduce risk of severe exacerbations.

Step 2: Regular low dose ICS plus as-needed SABA. Other options: LTRA are less effective than ICS; ICS/LABA leads to faster improvement in symptoms and FEV1 than ICS alone but is more expensive and then exacerbation rate is similar. For purely seasonal allergic asthma, start ICS immediately and cease 4 weeks after end of exposure.

Step 3: Low dose ICS/LABA either as maintenance treatment plus as-needed SABA, or as ICS/formoterol maintenance and relieve therapy. For patients with at least 1 exacerbation in the last yer, low dose BDP/formoterol or BUD/formoterol maintenance and reliever strategy is more effective than maintenance ICS/LABA with as-needed SABA. Other options: medium dose ICS; for adult patients with rhinitis and allergic to house dust mite with exacerbations despite ICS, consider adding sublingual immunotherapy, provided FEV1 is 70% predicted. For children between 6 and 11: medium dose ICS. Other options include low dose ICS/LABA

Step 4: Low dose ICS/formoterol maintenance and reliever therapy, or medium dose ICS/LABA as maintenance plus as-needed SABA. Other options: add-on tiotropium by mist inhaler for patients of at least 12 years with a history of exacerbations; high dose ICS/LABA, but more side-effects and little extra benefit; extra controller; for adult patients with rhinitis and allergic to HDM with exacerbations despite ICS, consider adding SLIT, provided FEV1 is greater than 70% predicted. Children between 6 and 11: refer for expert assessment and advice.

Step 5: Refer for expert investigation and add-on treatment. Add-on treatments include tiotropium by mist inhaler for patients with a history of exacerbation (of at least 12 years old), anti-IgE (SC omalizumab) for severe allergic asthma of at least 6 years old, and anti-IL5 for severe eosinophilic asthma (SB mepolizumab or SC benralizumab for age 12 years or older or IV reslizumab for at 18 years or older). Sputum-guided treatment, if available, improves outcomes. Other options: some patients may benefit from low dose OCS but long-term systemic side-effects commonly occur.


Adopted from Global Initiative for Asthma Guidelines 2018.


APPENDIX B: Classifying Asthma Severity and Initiating Treatment in Youths ≥12 Years of Age and Adults.
Assessing severity and initiating treatment for patients who are not currently taking long-term control medications.



Components of Severity	Classification of Asthma Severity (≥12 years of age)
	Intermittent	Persistent
		Mild	Moderate	Severe
Impairment:
Symptoms	≤2 days/week	>2 days/week but not daily	Daily	Throughout the day
Nighttime awakenings	≤2x/month	3-4 4x/month	>1x/week but not nightly	Often 7x/week
Short-acting beta2-agonist use for symptom control (not for prevention of EIB)	≤2 days/week	>2 days/week but not daily, and not more than 1x on any day	Daily	Several times per day
Interference with normal activity	None	Minor limitation	Some limitation	Extremely limited
Lung function	Normal FEV1 between exacerbations FEV1 >80% predicted FEV1/FVC normal	FEV1>80% predicted FEV1/FVC normal	FEV1>60% but <80% predicted FEV1/FVC reduced 5%	FEV1<60% predicted FEV1/FVC reduced >5%
Risk:
Exacerbations requiring oral systemic corticosteroids	0-1/year (see note)	≥2/year (see note)
	Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category. Relative annual risk of exacerbations may be related to FEV1.
Recommended Step for Initiating Treatment (See Appendix A for treatment steps)	Step 1	Step 2	Step 3	Step 4 or 5
			and consider short course of oral systemic corticosteroids
	In 2-6 weeks, evaluate level of asthma control that is achieved and adjust therapy accordingly.
Key: FEV1 - forced expiratory volume in 1 second; FVC - forced vital capacity; ICU - intensive care unit Normal FEV1/FVC: 8-19 yr = 85%; 20-39 yr = 80%; 40-59 yr = 75%; 60-80 y r= 70% Notes: The stepwise approach is meant to assist, not replace the clinical decision-making required to meet individual patient needs. Level of severity is determined by assessment of both impairment and risk. Assess impairment domain by patient's/caregiver's recall of previous 2-4 weeks and spirometry. Assign severity to the most severe category in which any feature occurs. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had >2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma.

Adopted from the National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the Diagnosis and
Management of Asthma. 2007.


APPENDIX C: Assessing Asthma Control and Adjusting Therapy in Youths >12 Years of Age and Adults.

Components of Control	Classification of Asthma Control (>12 years of age)
	Well Controlled	Not Well Controlled	Very Poorly Controlled
Impairment:
Symptoms	≤2 days/week	>2 days/week	Throughout the day
Nighttime awakenings	≤2x/month	1-3x/week	≥4x/week
Interference with normal activity	None	Some limitation	Extremely limited
Short-acting beta2-agonist use for symptom control (not prevention of EIB)	≤2 days/week	>2 days/week	Several times per day
FEV1 or peak flow	>80% predicted/ personal best	60-80% predicted/ personal best	<60% predicted/ personal best
Validated questionnaires: ATAQ ACQ ACT	0 ≤0.75* >20	1-2 >1.5 16-19	3-4 N/A ≤15
Risk:
Exacerbations requiring oral systemic corticosteroids	0-1/year	>2/year (see note)
	Consider severity and interval since last exacerbation
Progressive loss of lung function	Evaluation requires long-term follow-up
Treatment-related adverse effects	Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment.
Recommended Action for Treatment (see Appendix A for treatment steps)	Maintain current step, Regular follow-ups every 1-6 months to maintain control Consider step down if well controlled for at least 3 months.	Step up 1 step and Re-evaluate in 2-6 weeks. For side effects, consider alternative treatment options.	Consider short course of oral systemic corticosteroids Step up 1-2 steps, and Re-evaluate in 2 weeks. For side effects, consider alternative treatment options.
*ACQ values of 0.76-1.4 are indeterminate regarding well-controlled asthma. Key: EIB - exercise-induced bronchospasms; ICU - intensive care unit Notes: The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient's recall of previous 2-4 weeks and by spirometry peak flow measures. Symptom assessment for longer periods should reflect a global assessment, such as inquiring whether the patient's asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had >2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma. Validated Questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain): ATAQ = Asthma Therapy Assessment Questionnaires ACQ = Asthma Control Questionnaires ACT = Asthma Control Test Before step up in therapy: -- Review adherence to medication, inhaler technique, environmental control, and co-morbid conditions. -- If an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step.

Adopted from the National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007.

APPENDIX D: Estimated Comparative Daily Dosages for Inhaled Corticosteroids for Youths ≥12 Years of Age and Adults

Drug	Low Daily Dose Adult	Medium Daily Dose Adult	High Daily Dose Adult
Beclamethasone HFA 40 or 80 mcg/puff	80-240 mcg	>240-480 mcg	>480 mcg
Budesonide DPI 90, 180, or 200 mcg/inhalation	180-600 mcg	>600-1,200 mcg	>1,200 mcg
Flunisolide 250 mcg/puff	500-1,000 mcg	>1,000-2,000 mcg	>2,000 mcg
Flunisolide FHA 80 mcg/puff	320 mcg	>320-640 mcg	>640 mcg
Fluticasone HFA/MDI: 44, 110, ir 220 mcg/inhalation DPI: 50, 100, or 250 mcg/inhalation	88-264 mcg 100-300 mcg	>264-440 mcg >300-500 mcg	>440 mcg >500 mcg
Mometasone DPI 200 mcg/inhalation	200 mcg	400 mcg	>400 mcg
Mometasone/Formoterol DPI 100 mcg/5mcg and 200 mcg/5 mcg inhalation	200 mcg	400 mcg	> 400 mcg
Triamcinolone acetonide 75 mcg/puff	300-750 mcg	>750-1,500 mcg	>400 mcg
Key: DPI - dry powder inhaler; HFA - hydrofluoroalkane; MDI: metered-dose inhaler Note: The most important determinant of appropriate dosing is the clinician's judgement of the patient's response to therapy. The clinician must monitor the patient's response on several clinical parameters and adjust the dose accordingly. The stepwise approach to therapy emphasized that once control of asthma is achieved, the dose of medication should be carefully titrated to the minimum dose required to maintain control, thus reducing the potential for adverse effect.

Adopted from the National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007.

There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a coverage determination specific to these drugs. Since there is no policy specific to Nucala, Cinqair, and Fasenra, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy. See generally Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53049&ver=44&name=314*1&UpdatePeriod=711&bc=AQAAEAAAAAAAAA%3d%3d&

Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them. Therefore, Medicare Advantage Products will cover Nucala, Cinqair, and Fasenra when administered by a licensed medical provider as part of a physician service when the Horizon BCBSNJ Medical policy criteria is met.

**Note: Bullet 1 of the policy section referring to Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) does not apply for Medicare Advantage Products.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Mepolizumab (Nucala)
Nucala (mepolizumab)
Monoclonal Interleukin-5 Antagonists
reslizumab (Cinqair)
Cinqair (reslizumab)
Benralizumab (Fasenra)
Fasenra (benralizumab)

References:
1. Nucala Dossier. Glaxosmithkline. 2015.

2. Nucala [Prescribing information]. Glaxosmithkline. Philadelphia, PA. September 2019.

3. Nucala Advisory Committee. Food and Drug Administration. 2015. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM450248.pdf

4. National Heart, Lung and Blood Institute and the National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. U.S. Department of Health and Human Services; 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

5. Cinqair [Prescribing information] Teva Respiratory, LLC. Frazer, PA. March 2016.

6. Castro M, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet Respiratory Med. 2015; 3:355-66.

7. Cinqair FDA Advisory Committee for BLA 761033: Reslizumab for intravenous injection. Food and Drug Administration [Online]. December 2015. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM475759.pdf

8. Fasenra [Prescribing information]. AstraZeneca. Wilmongton, DE. October 2019.

9. Bleeker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting b₂-agonists (SIROCCO): a randomized, multicenter, placebo-controlled phase 3 trial. Lancet. 2016; 388:2115-2127.

10. FitzGerald JM, Bleeker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor a monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388: 2128-2141.

11. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017; 376: 2448-2458.

12. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017;376(20):1921-1932.

13. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. Available from: www.ginasthma.org. Accessed February 2019.

14. Nucala is the First Biologic Approved in the US for Six to 11 year old Children with Severe Eosinophilic Asthma. Glaxo Smith-Kline. September 27, 2019. Accessed September 27, 2019. https://www.gsk.com/en-gb/media/press-releases/nucala-is-the-first-biologic-approved-in-the-us-for-six-to-11-year-old-children-with-severe-eosinophilic-asthma/

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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