Tezacaftor/Ivacaftor; Ivacaftor (Symdeko) Form

Tezacaftor/ivacaftor; ivacaftor (Symdeko®) is a combination drug for cystic fibrosis (CF).
• Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of cystic fibrosis transmembrane conductance regulator [CFTR; (including F508del- CFTR)] to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface.
• • The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport. FDA Approved Indication(s) Symdeko is indicated for the treatment of patients with CF aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
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 Symdeko 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, and c): 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 E): 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; ≥ Page 1 of 8

   CLINICAL POLICY Tezacaftor/Ivacaftor; Ivacaftor c. One of the following (i or ii): i. Confirmation member is homozygous for the F508del mutation in the CFTR gene; ii. Presence of at least one mutation in the CFTR gene that is responsive to Symdeko based on in vitro data and/or clinical evidence (see Appendix D);

2. Age ≥ 6 years;
   3. Prescribed by or in consultation with a pulmonologist;
   4. Chart notes indicate that pulmonary function tests, performed within the last 90 days, show a percent predicted forced expiratory volume in 1 second (ppFEV1) that is between 40-90%;
3. Symdeko is not prescribed concurrently with other CFTR modulators (e.g., Kalydeco®, Orkambi®, Trikafta™);
4. Dose does not exceed any of the following (a or b): a. Age 6 to < 12 years weighing < 30 kg (both i and ii): i. Tezacaftor 50 mg/ivacaftor 150 mg; ii. 1 tablet tezacaftor/ivacaftor and 1 tablet ivacaftor; b. Age 6 to < 12 years weighing ≥ 30 kg and ≥ 12 years (both i and ii): i. Tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 1 tablet tezacaftor/ivacaftor and 1 tablet ivacaftor per day. Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):
5. 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
6. 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.
   II. Continued Therapy A. Cystic Fibrosis (must meet all):

7. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; Page 2 of 8

   CLINICAL POLICY Tezacaftor/Ivacaftor; Ivacaftor 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);

8. Member is responding positively to therapy as evidenced by a stabilization in ppFEV1 if baseline was ≥ 70% or increase in ppFEV1 if baseline was < 70%;
9. Symdeko is not prescribed concurrently with other CFTR modulators (e.g., Kalydeco®, Orkambi®, Trikafta™);
10. If request is for a dose increase, new dose does not exceed any of the following (a or b): a. Age 6 to < 12 years weighing < 30 kg (both i and ii): i. Tezacaftor 50 mg/ivacaftor 150 mg; ii. 1 tablet tezacaftor/ivacaftor and 1 tablet ivacaftor; b. Age 6 to < 12 years weighing ≥ 30 kg and ≥ 12 years (both i and ii): i. Tezacaftor 100 mg/ivacaftor 300 mg per day; ii. 1 tablet tezacaftor/ivacaftor and 1 tablet ivacaftor per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):
11. 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

12. 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 CFTR: cystic fibrosis transmembrane conductance regulator FDA: Food and Drug Administration Page 3 of 8

    CLINICAL POLICY Tezacaftor/Ivacaftor; Ivacaftor ppFEV1: percent predicted forced expiratory volume in 1 second Appendix B: Therapeutic Alternatives
    Not applicable
    Appendix C: Contraindications/Boxed Warnings None reported Appendix D: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to Symdeko CFTR Gene Mutations that Produce CFTR Protein and are Responsive to Symdeko E92K 546insCTA E116K 711+3A→G E193K 2789+5G→A 3272-26A→G E403D 3849+10kbC→T E588V E822K A120T E831X A234D F191V A349V F311del A445E F311L A554E F508C A1006E F508C; A1067T S1251N† F508del F575Y F1016S F1052V G576A
    L346P G576A;R668C† L967S L997F G622D L1324P G970D L1335P G1069R L1480P G1244E M152V G1249R M265R G1349D M9521 H939R M952T H1054D P5L H1375P S589N S737F S912L S945L S977F S1159F S1159P S1251N S1255P T338I T1036N R117G R117H R117L R117P R170H R258G R334L R334Q R347H R347L R347P P205S Q98R Q237E Q237H R352W R553Q R668C R751L V201M V232D V562I V754M I175V I336K I601F I618T T1053I R352Q 1148T P67L F1074L I807M Q359R R792G V1153E F1099L G126D G178E G178R I980K I1027T I1139V I1269N G194R I1366N G194V K1060T G314E L15P R933G V1240G R1066H V1293G R1070Q W1282R R1070W Y109N R1162L Y161S R1283M Y1014C R1283S Y1032C Q1291R R31L R74Q R74W R74W; D1270N† R74W; V201M† R74W;V201M; D1270N† R75Q R117C E56K E60K A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in this table to be indicated. G551D G551S L206W L320V S549N S549R D110E D110H D192G D443Y D443Y;G576A; R668C† D579G D614G D836Y D924N D979V D1152H D1270N Page 4 of 8

    CLINICAL POLICY Tezacaftor/Ivacaftor; Ivacaftor CFTR Gene Mutations that Produce CFTR Protein and are Responsive to Symdeko † 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. Appendix E: 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. • 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. • Cystic Fibrosis Foundation 2020 guidelines for advanced cystic fibrosis lung disease (ACFLD): o Define ACFLD as ppFEV1 < 40% when stable or referred for lung transplantation evaluation or previous intensive care unit (ICU) admission for respiratory failure, hypercarbia, daytime oxygen requirement at rest (excluding nocturnal use only), pulmonary hypertension, severe functional impairment from respiratory disease (New York Heart Association Class IV), six-minute walk test distance < 400m.
    o No recommendations on the start or continuation of CFTR modulator therapy with ACFLD guidelines.
    o Treatment recommendations included: lung transplantation, supplemental oxygen, continuous alternating inhaled antibiotics, and systemic corticosteroids V. Dosage and Administration
    Indication Dosing Regimen CF Pediatric patients age 6 to < 12 years weighing < 30 kg: one tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 75 mg) in the evening, approximately 12 hours apart with fat- containing food. Adults and pediatric patients age 12 years and older or pediatric patients age 6 to < 12 years weighing 30 kg or more: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart with fat-containing food. Maximum Dose Age 6 to < 12 years weighing < 30 kg: Tezacaftor 50mg/ivacaftor 150 mg Age 6 to < 12 years weighing 30 kg or more and age > 12 years: Page 5 of 8

    CLINICAL POLICY Tezacaftor/Ivacaftor; Ivacaftor Indication Dosing Regimen Reduce dose in patients with moderate and severe hepatic impairment. Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.
    Maximum Dose tezacaftor 100 mg/ivacaftor 300 mg per day VI. Product Availability
    Tablets: co-packaged as tezacaftor 50 mg/ivacaftor 75 mg fixed dose combination tablets with ivacaftor 75 mg tablets OR tezacaftor 100 mg/ivacaftor 150 mg fixed dose combination tablets with ivacaftor 150 mg tablets
    VII.