SPORANOX, Itraconazole ONMEL, Itraconazole TOLSURA, Itraconazole Form

Itraconazole (Sporanox®, Tolsura®) is an azole antifungal agent. FDA Approved Indication(s) Sporanox and Tolsura capsules are indicated in: • Immunocompromised and non-immunocompromised patients for the treatment of: o Blastomycosis, pulmonary and extrapulmonary o Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis o Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy Sporanox capsules are additionally indicated in: • Non-immunocompromised patients for the treatment of: o Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) o Onychomycosis of the fingernail due to dermatophytes (tinea unguium) Sporanox oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis. Limitation(s) of use: Tolsura is not indicated for the treatment of onychomycosis. Tolsura is not interchangeable or substitutable with other itraconazole products.
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 Sporanox and Tolsura are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Onychomycosis (must meet all):

1. Diagnosis of onychomycosis;
2. Request is for Sporanox or itraconazole capsules;

3. If request is for brand Sporanox, member must use generic itraconazole capsules, unless contraindicated or clinically significant adverse effects are experienced; Page 1 of 14

   CLINICAL POLICY Itraconazole

   4. Member meets one of the following (a or b): a. For fingernail disease: Failure of a 6-week trial of oral terbinafine at 250 mg per day, unless contraindicated or clinically significant adverse effects are experienced; b. For toenail disease: Failure of a 12-week trial of oral terbinafine at 250 mg per day, unless contraindicated or clinically significant adverse effects are experienced;
   5. Dose does not exceed 400 mg (4 capsules) per day. Approval duration: Fingernail disease: 2 months; toenail disease: 3 months B. Oropharyngeal Candidiasis (must meet all):
4. Diagnosis of oropharyngeal candidiasis;
5. Request is for Sporanox or itraconazole oral solution;
6. If request is for brand Sporanox, member must use generic itraconazole oral solution, unless contraindicated or clinically significant adverse effects are experienced;
   4. Failure of a 7-day trial of nystatin suspension or clotrimazole troches/lozenges, unless clinically significant adverse effects are experienced or both are contraindicated;
7. Failure of a 7-day trial of fluconazole, unless contraindicated or clinically significant adverse effects are experienced;
   6. Dose does not exceed 200 mg (20 mL) per day. Approval duration: 4 weeks C. Esophageal Candidiasis (must meet all):
8. Diagnosis of esophageal candidiasis;
9. Request is for Sporanox or itraconazole oral solution;
10. If request is for brand Sporanox, member must use generic itraconazole oral solution, unless contraindicated or clinically significant adverse effects are experienced;
11. Failure of a 14-day trial of fluconazole at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
    5. Dose does not exceed 200 mg (20 mL) per day. Approval duration: 4 weeks D. Aspergillosis (must meet all):
12. Diagnosis of aspergillosis;
13. Request is for Sporanox, Tolsura, or itraconazole capsules;
14. If request is for brand Sporanox or Tolsura, member must use generic itraconazole capsules, unless contraindicated or clinically significant adverse effects are experienced;
    4. Failure of a 3-month trial of voriconazole at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for voriconazole

15. Dose does not exceed one of the following (a or b): a. Itraconazole or Sporanox capsules: 400 mg (4 capsules) per day; b. Tolsura capsules: 260 mg (4 capsules) per day. Approval duration: 3 months Page 2 of 14

    CLINICAL POLICY Itraconazole E. Blastomycosis or Histoplasmosis (must meet all):

16. Diagnosis of blastomycosis or histoplasmosis;
17. Request is for Sporanox, Tolsura, or itraconazole capsules;
18. If request is for brand Sporanox or Tolsura, member must use generic itraconazole capsules, unless contraindicated or clinically significant adverse effects are experienced;
    4. Dose does not exceed one of the following (a or b): a. Itraconazole or Sporanox capsules: 400 mg (4 capsules) per day; b. Tolsura capsules: 260 mg (4 capsules) per day. Approval duration: Blastomycosis: 6 months; Histoplasmosis: 6 weeks F. Hematologic Malignancy (off-label) (must meet all):
    5. Diagnosis of hematologic malignancy;
19. Member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;
    3. Member meets one of the following (a or b): a. Request is for prophylaxis of aspergillosis;
       b. Request is for prophylaxis of candidiasis, and member has failed fluconazole at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
    4. Dose does not exceed one of the following (a, b, or c): a. Itraconazole or Sporanox capsules: 400 mg (4 capsules) per day; b. Itraconazole or Sporanox oral solution: 200 mg (20 mL) per day; c. Tolsura capsules: 260 mg (4 capsules) per day. Approval duration: 3 months G. Coccidioidomycosis (off-label) (must meet all):
    5. Diagnosis of coccidioidomycosis infection, and member is infected with one of the following (a, b, or c): a. HIV-1, and member has peripheral blood CD4 < 250 cells/mm3; b. Focal pulmonary disease; c. Disseminated extrathoracic nonmeningeal or meningeal coccidioidomycosis;
    6. Request is for Sporanox or itraconazole capsules or oral solution;
20. Prescribed by or in consultation with an infectious disease specialist, pulmonologist, or HIV specialist;
    4. If request is for brand Sporanox, member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;
    5. Failure of fluconazole at up to maximally indicated doses, unless contraindicated or clinically significant adverse effects are experienced;

21. Dose does not exceed one of the following (a, b, or c): a. For disseminated extrathoracic nonmeningeal or meningeal coccidioidomycosis (i or ii):
    i. Capsules: 600 mg (6 capsules) per day; ii. Oral solution: 600 mg (60 mL) per day; Page 3 of 14

    CLINICAL POLICY Itraconazole b. For coccidioidomycosis with HIV-1 co-infection (i or ii): i. Capsules: 600 mg (6 capsules) per day for the first three days, then 400 mg (4 capsules) per day thereafter; ii. Oral solution: 600 mg (60 mL) per day for the first three days, then 400 mg (40 mL) per day thereafter; c. For all other coccidioidomycosis infections (i or ii):
    i. Capsules: 400 mg (4 capsules) per day; ii. Oral solution: 400 mg (40 mL) per day. Approval duration: 6 months H. Sporotrichosis (off-label) (must meet all):

    1. Diagnosis of sporotrichosis infection, and member is infected with one of the following (a or b): a. Lymphocutaneous, cutaneous, non-severe pulmonary or osteoarticular sporotrichosis; b. Severe pulmonary, meningeal, or disseminated systemic sporotrichosis;
    2. Request is for Sporanox or itraconazole capsules or oral solution;

22. Prescribed by or in consultation with an infectious disease specialist or pulmonologist;

    4. If request is for brand Sporanox, member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;
    5. For severe pulmonary, meningeal, or disseminated systemic sporotrichosis: Previous use of amphotericin B, unless contraindicated or clinically significant adverse effects are experienced;
    6. Dose does not exceed one of the following (a or b): a. Capsules: 400 mg (4 capsules) per day; b. Oral solution: 400 mg (40 mL) per day. Approval duration: 12 months I. Other diagnoses/indications (must meet 1 or 2):
    7. 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
    8. 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 4 of 14

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

    1. 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);
23. Member is responding positively to therapy;
24. Request is for Sporanox or itraconazole capsules;
25. If request is for brand Sporanox, member must use generic itraconazole capsules, unless contraindicated or clinically significant adverse effects are experienced;
    5. Member has not received more than 90 days of treatment;
26. If request is for a dose increase, new dose does not exceed 400 mg (4 capsules) per day. Approval duration: Fingernail disease: up to 2 months total; toenail disease: up to 3 months total
    B. Oropharyngeal/Esophageal Candidiasis (must meet all):
    
    1. 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);
27. Member is responding positively to therapy;
28. Request is for Sporanox or itraconazole oral solution;
29. If request is for brand Sporanox, member must use generic itraconazole oral solution, unless contraindicated or clinically significant adverse effects are experienced;
30. If request is for a dose increase, new dose does not exceed 200 mg (20 mL) per day. Approval duration: 2 weeks C. Blastomycosis, Histoplasmosis, or Aspergillosis (must meet all):
    1. 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);
31. Member is responding positively to therapy;
32. Request is for Sporanox, Tolsura, or itraconazole capsules;

33. If request is for brand Sporanox, member must use generic itraconazole capsules, unless contraindicated or clinically significant adverse effects are experienced; Page 5 of 14

    CLINICAL POLICY Itraconazole

    5. If request is for a dose increase, new dose does not exceed one of the following (a or b):
       a. Itraconazole or Sporanox capsules: 400 mg (4 capsules) per day; b. Tolsura capsules: 260 mg (4 capsules) per day. Approval duration: Blastomycosis: 6 months; Histoplasmosis: 6 weeks; Aspergillosis: 3 months D. Hematologic Malignancy (off-label) (must meet all):
34. 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);
    2. Member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;
    3. Member is responding positively to therapy;
35. If request is for a dose increase, new dose does not exceed one of the following (a, b, or c):
    a. Itraconazole or Sporanox capsules: 400 mg (4 capsules) per day; b. Itraconazole or Sporanox oral solution: 200 mg (20 mL) per day; c. Tolsura capsules: 260 mg (4 capsules) per day. Approval duration: 6 months E. Coccidioidomycosis (off-label) (must meet all):
36. 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);
    2. Request is for Sporanox or itraconazole capsules or oral solution;
37. If request is for brand Sporanox, member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;
    4. If HIV-1 positive, member has peripheral blood CD4 < 250 cells/mm3;

38. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. For disseminated extrathoracic nonmeningeal or meningeal coccidioidomycosis (i or ii):
    i. Capsules: 600 mg (6 capsules) per day; ii. Oral solution: 600 mg (60 mL) per day; b. For all other coccidioidomycosis infections (i or ii):
    i. Capsules: 400 mg (4 capsules) per day; ii. Oral solution: 400 mg (40 mL) per day. Approval duration: 12 months Page 6 of 14

    CLINICAL POLICY Itraconazole F. Sporotrichosis (off-label) (must meet all):

    1. 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);
    2. Request is for Sporanox or itraconazole capsules or oral solution;

39. If request is for brand Sporanox, member must use generic itraconazole capsules or oral solution, unless contraindicated or clinically significant adverse effects are experienced;

    4. If request is for a dose increase, new dose does not exceed one of the following (a or b): a. Capsules: 400 mg (4 capsules) per day; b. Oral solution: 400 mg (40 mL) per day. Approval duration: 12 months G. 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.
       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 CHF: congestive heart failure FDA: Food and Drug Administration Page 7 of 14

    CLINICAL POLICY Itraconazole Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen terbinafine (Lamisil®) nystatin suspension
    250 mg PO QD
    400,000 to 600,000 units (4 to 6 mL) per dose swished in the mouth QID 10 mg troche PO 5 times daily for 14 days 400 mg PO per day clotrimazole troches/ lozenges (Mycelex®) fluconazole (Diflucan®) voriconazole (Vfend®) Weight ≥ 40 kg: 200 mg PO every 12 hours Weight < 40 kg: 100 mg PO every 12 hours Adults: 0.7 to 1 mg/kg/dose IV every 24 hours until favorable response. Continue step-down therapy with itraconazole to complete a total of at least 12 months of therapy amphotericin B Dose Limit/ Maximum Dose 500 mg per day 2.4 million units per day Varies 800 mg per day Weight ≥ 40 kg: 800 mg per day
    Weight < 40 kg: 400 mg per day 1 – 1.5 mg/kg/day IV Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Itraconazole should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. o Concomitant coadministration of itraconazole with the following drugs: methadone, dofetilide, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), felodipine, pimozide, oral midazolam, triazolam, nisoldipine, cisapride, lovastatin, simvastatin. o Additional product-specific drug-drug interactions include:  Sporanox (capsules and oral solution), Tolsura: disopyramide, dronedarone, irinotecan, lurasidone, ivabradine, ranolazine, eplerenone, ticagrelor and, in subjects with varying degrees of renal or hepatic impairment, colchicine, fesoterodine, and solifenacin.
     Sporanox capsules: telithromycin  Sporanox oral solution, Tolsura: isavuconazole, naloxegol, lomitapide, avanafil o Treatment of onychomycosis in women who are pregnant or contemplating pregnancy o Hypersensitivity and anaphylaxis to itraconazole Page 8 of 14

    CLINICAL POLICY Itraconazole • Boxed warning(s):
    o CHF or history of CHF (see contraindications) o Drug-drug interactions (see contraindications) V. Dosage and Administration
    Drug Name Indication Dosing Regimen Itraconazole (Sporanox) capsule Blastomycosis Histoplasmosis Aspergillosis Onychomycosis 200 mg PO QD 200 mg PO QD 200 to 400 mg PO QD 200 mg PO QD for 12 weeks (toenails with or without fingernail involvement) 200 mg PO BID for 1 week, followed by no drug for 3 weeks, then another week of 200 mg PO BID or 200 mg PO QD for 6 weeks (fingernails only) Maximum Dose 400 mg/day 400 mg/day 400 mg/day 400 mg/day Coccidioidomycosis 200 mg PO BID or 200 mg BID- 600 mg/day Lymphocutaneous or cutaneous sporotrichosis Osteoarticular, pulmonary, meningeal, or disseminated systemic sporotrichosis In life-threatening situations Oropharyngeal candidiasis Itraconazole (Sporanox) oral solution TID for nonmeningeal or meningeal coccidioidomycosis In patients co-infected with HIV: Adults: 200 mg PO TID for the first 3 days, then 200 mg PO BID Pediatrics: 5-10 mg/kg PO BID for the first 3 days, then 2-5 mg/kg PO BID 200 mg PO QD for 3-6 months. If no response then increase to 200 mg PO BID. 200 mg PO BID for at least 12 months 400 mg/day 400 mg/day Loading dose of 200 mg PO TID given for the first 3 days of treatment 200 mg (20 mL) PO daily for 1 to 2 weeks; swish in the mouth (10 mL at a time) for several seconds and swallow 600 mg/day 200 mg
    (20 mL)/day
    Page 9 of 14

    CLINICAL POLICY Itraconazole Drug Name Indication Dosing Regimen Coccidioidomycosis 200 mg (20 mL) PO BID or 200 mg (20 mL) BID-TID for nonmeningeal or meningeal coccidioidomycosis Maximum Dose 600 mg (60 mL)/day 400 mg (40 mL)/day 400 mg (40 mL)/day In patients co-infected with HIV: Adults: 200 mg PO TID for the first 3 days, then 200 mg PO BID Pediatrics: 5-10 mg/kg PO BID for the first 3 days, then 2-5 mg/kg PO BID 200 mg (20 mL) PO QD for 3-6 months. If no response then increase to 200 mg PO BID. 200 mg (20 mL) PO BID for at least 12 months 100 mg (10 mL) PO daily for a minimum treatment of three weeks 130 mg PO QD. Increase dose if no obvious improvement or evidence of progressive fungal disease in 65 mg increments. Doses above 130 mg/day should be given in divided doses. 130 mg PO QD or BID 200 mg
    (20 mL)/day
    260 mg/day 260 mg/day Lymphocutaneous or cutaneous sporotrichosis Osteoarticular, pulmonary, meningeal, or disseminated systemic sporotrichosis Esophageal candidiasis Blastomycosis, histoplasmosis
    Aspergillosis Itraconazole (Tolsura) VI. Product Availability
    Drug Name Itraconazole (Sporanox) Itraconazole (Tolsura) Availability Capsule: 100 mg Oral solution: 10 mg/mL Capsule: 65 mg VII.