KALYDECO, Ivacaftor Form

Ivacaftor (Kalydeco®) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. FDA Approved Indication(s) Kalydeco is indicated for the treatment of cystic fibrosis (CF) in patients age 1 month and older who have one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Kalydeco is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Cystic Fibrosis (must meet all):

1. Diagnosis of CF confirmed by all of the following (a, b, c, and d): a. Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or genetic testing for siblings of patients with CF; b. Evidence of CFTR dysfunction confirmed by one of the following (i or ii) (see Appendix D): i. Elevated sweat chloride ii. Genetic testing confirming the presence of two disease-causing mutations in 60 mmol/L; CFTR gene, one from each parental allele; ≥ c. Presence of one mutation in the CFTR gene responsive to ivacaftor based on clinical and/or in vitro assay data (see Appendix E); d. Confirmation that a homozygous F508del mutation in the CFTR gene is not present;

2. Age ≥ 1 month;

   3. Prescribed by or in consultation with a pulmonologist; Page 1 of 10

   CLINICAL POLICY Ivacaftor

3. Documentation of one of the following pulmonary function tests performed within the last 90 days (a or b, see Appendix D): a. Member’s baseline percent predicted forced expiratory volume in 1 second (ppFEV1); b. For age < 6 years: Lung clearance index (LCI) that is ≥ 7.4;
4. Kalydeco is not prescribed concurrently with other CFTR modulators (e.g., Orkambi®, Symdeko®, Trikafta™);
5. Dose does not exceed one of the following (a, b, c, d, e, f, or g): a. Age 1 month to < 2 months and weight ≥ 3 kg (both i and ii):
   i. 11.6 mg per day; ii. 2 packets per day; b. Age 2 months to < 4 months and weight ≥ 3 kg (both i and ii): i. 26.8 mg per day; ii. 2 packets per day; c. Age 4 months to < 6 months and weight ≥ 5 kg (both i and ii):
   i. 50 mg per day; ii. 2 packets per day; d. Age 6 months to < 6 years and weight 5 kg to < 7 kg (both i and ii):
   i. 50 mg per day; ii. 2 packets per day; e. Age 6 months to < 6 years and weight 7 kg to < 14 kg (both i and ii):
   i. 100 mg per day; ii. 2 packets per day; f. Age 6 months to < 6 years and weight ≥ 14 kg (both i and ii):
   i. 150 mg per day; ii. 2 packets per day; g. Age ≥ 6 years (both i and ii):
   i. 300 mg per day; ii. 2 tablets per day. Approval duration: 6 months
   B. Other diagnoses/indications (must meet 1 or 2):
6. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

7. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line Page 2 of 10

   CLINICAL POLICY Ivacaftor of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Cystic Fibrosis (must meet all):

8. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
9. Member is responding positively to therapy as evidenced by one of the following (a or b): a. Stabilization or improvement in ppFEV1;
   b. For age < 6 years: Stabilization or decrease in LCI from baseline;
10. Kalydeco is not prescribed concurrently with other CFTR modulators (e.g., Orkambi, Symdeko, Trikafta);
11. If request is for a dose increase, new dose does not exceed one of the following (a, b, c, d, e, f, or g): a. Age 1 month to < 2 months and ≥ 3 kg (both i and ii):
    i. 11.6 mg per day; ii. 2 packets per day; b. Age 2 months to < 4 months and ≥ 3 kg (both i and ii): i. 26.8 mg per day; ii. 2 packets per day; c. Age 4 months to < 6 months and weight ≥ 5 kg (both i and ii):
    i. 50 mg per day; ii. 2 packets per day; d. Age 6 months to < 6 years and weight 5 kg to < 7 kg (both i and ii):
    i. 50 mg per day; ii. 2 packets per day; e. Age 6 months to < 6 years and weight 7 kg to < 14 kg (both i and ii):
    i. 100 mg per day; ii. 2 packets per day; f. Age 6 months to < 6 years and weight ≥ 14 kg (both i and ii):
    i. 150 mg per day; ii. 2 packets per day; g. Age ≥ 6 years (both i and ii):
    i. 300 mg per day; ii. 2 tablets per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):

12. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): Page 3 of 10

    CLINICAL POLICY Ivacaftor a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

13. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ACFLD: advanced cystic fibrosis lung disease
    CF: cystic fibrosis CFF: Cystic Fibrosis Foundation CFTR: cystic fibrosis transmembrane conductance regulator Appendix B: Therapeutic Alternatives
    Not applicable FDA: Food and Drug Administration LCI: lung clearance index MAP: Mutation Analysis Program
    MBW: multiple-breath washout ppFEV1 : percent predicted forced expiratory volume in 1 second Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • The Cystic Fibrosis Foundation (CFF) Mutation Analysis Program (MAP) available here: https://www.cff.org/medical-professionals/mutation-analysis-program. The MAP is a free and confidential genetic testing program for people with a strongly suspected or confirmed diagnosis of CF. • Kalydeco is not effective in patients with CF who are homozygous for the F508del • mutation in the CFTR gene. It is recommended that transaminases (ALT and AST) be assessed prior to initiating Kalydeco, every 3 months during the first year of treatment, and annually thereafter. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal. Page 4 of 10

    CLINICAL POLICY Ivacaftor • Data from the study of CF patients with nine CFTR mutations did not support approval of the drug in patients with the G970R mutation. As of 2014, it is estimated that there are about 10 people worldwide who have this mutation, including two in the United States. • Regarding the diagnostic criteria for CF of “genetic testing confirming the presence of two disease-causing mutations in CFTR gene,” this is to ensure that whether heterozygous or homozygous, there are two disease-causing mutations in the CFTR gene, one from each parental allele. • Most children can do spirometry by age 6, though some preschoolers are able to perform the test at a younger age. Some young children aren’t able to take a deep enough breath and blow out hard and long enough for spirometry. Forced oscillometry is another way to test lung function in young children. This test measures how easily air flows in the lungs (resistance and compliance) with the use of a machine. • The two most commonly reported parameters from multiple-breath washout (MBW) tests are the lung clearance index (LCI) and moment ratios (MRs). Measurements of LCI and MR are taken during the washout period. During the washout phase, subjects inhale gases that do not contain the test gas of interest. The principles of the washout are the same regardless of the test gas measured. The washout is stopped once the test gas reaches 1/40 of the initial gas concentration • NHS Clinical Guidelines: Care of Children with Cystic Fibrosis: Normal ranges for LCI are device specific and still being established, but in general a value > 8.0 is above the normal range and > 10.0 is significantly abnormal. † F311del F311L F508C Appendix E: CFTR Gene Mutations that are Responsive to Kalydeco
    CFTR Gene Mutations that are Responsive to Kalydeco R75Q 711+3A→G R117C
    2789+5G→A R117G 3272-26A→G R117H
    3849+10kbC→T F508C; S1251N R117L A120T R117P A234D R170H A349V R347H
    A455E
    R347L A1067T R352Q
    D110E R553Q D110H R668C D192G R792G D579G
    R933G D924N R1070Q D1152H
    R1070W
    D1270N R1162L E56K R1283M E193K S549N
    E822K S549R
    E831X
    I148T I175V I807M I1027T I1139V K1060T L206W
    L320V L967S L997F L1480P M152V M952I M952T P67L
    Q237E Q237H Q359R Q1291R R74W F1052V F1074L G178E G178R
    G194R G314E G551D
    G551S
    G576A G970D G1069R G1244E
    G1249R G1349D
    H939R H1375P S589N S737F S945L
    S977F
    S1159F S1159P S1251N
    S1255P
    T338I T1053I V232D V562I V754M V1293G W1282R Y1014C Y1032C Page 5 of 10

    CLINICAL POLICY Ivacaftor † Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. V. Dosage and Administration
    Indication Dosing Regimen CF Pediatric patients 1 month to less than 2 months of age and weighing at least 3 kg: one 5.8 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat containing food. Maximum Dose Age 1 month to < 2 months and weight ≥ 3 kg: 11.8 mg/day Pediatric patients 2 months to less than 4 months of age and weighing at least 3 kg: one 13.4 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat containing food. Age 2 months to < 4 months and weight ≥ 3 kg: 26.8 mg/day Pediatric patients 4 months to less than 6 months of age and weighing at least 5 kg: one 25 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat containing food. Age 4 months to < 6 months and weight ≥ 5 kg: 50 mg/day Pediatric patients 6 months to less than 6 years of age weighing 5 kg to less than 7 kg: one 25 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat containing food.
    Age 6 months to < 6 years and weight 5 kg to < 7 kg: 50 mg/day Pediatric patients 6 months to less than 6 years of age weighing 7 kg to less than 14 kg: one 50 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat containing food.
    Pediatric patients 6 months to less than 6 years of age weighing 14 kg or greater: one 75 mg packet mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and PO every 12 hours with fat-containing food. Adults and pediatric patients age 6 years and older: one 150 mg tablet PO every 12 hours with fat- containing food.
    Age 6 months to < 6 years and weight 7 kg to < 14 kg: 100 mg/day Age 6 months to < 6 years and weight ≥ 14 kg: 150 mg/day Age ≥ 6 years:
    300 mg/day Page 6 of 10

    CLINICAL POLICY Ivacaftor VI. Product Availability
    • Tablet: 150 mg • Unit-dose packets (56 packets per carton) containing oral granules: 5.8 mg, 13.4 mg, 25 mg, 50 mg, 75 mg VII.