VALCYTE, Valganciclovir HCl Form

Valganciclovir (Valcyte®) is a deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor. ____ *For Health Insurance Marketplace (HIM), valganciclovir oral solution 50 mg/mL is non-formulary and should not be approved using these criteria; refer to the formulary exception policy, HIM.PA.103.
FDA Approved Indication(s) Valcyte is indicated for: • Adult patients
o Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). o For the prevention of CMV disease in kidney, heart, or kidney-pancreas transplant patients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]). • Pediatric patients
o Prevention of CMV disease in kidney transplant patients (4 months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high risk. 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 Valcyte is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. CMV Prophylaxis in Heart, Kidney, or Kidney-Pancreas Transplant (must meet all):

1. Member has a history of heart, kidney, or kidney-pancreas transplant;
   2. Organ donor or recipient is CMV seropositive;
   3. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;

2. Dose does not exceed 900 mg per day. Approval duration:
   Heart or kidney-pancreas transplant – 6 months Kidney transplant – 200 days (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) Page 1 of 10

   CLINICAL POLICY Valganciclovir B. CMV Retinitis (must meet all):

   1. Diagnosis of CMV retinitis;
   2. Prescribed by or in consultation with an ophthalmologist;
   3. Age > 16 years;
   4. Member is human immunodeficiency virus (HIV)-positive;
   5. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
3. Dose does not exceed the following: a. Induction: 1,800 mg per day for 21 days;
   b. Maintenance: 900 mg per day.
   Approval duration: 4 months (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) C. CMV Prophylaxis in Liver or Lung Transplant (off-label) (must meet all):
4. Member has a history of liver or lung transplant;
   2. Organ donor or recipient is CMV seropositive;
   3. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
5. Dose does not exceed 900 mg per day. Approval duration:
   Liver transplant – 6 months
   Lung transplant– 12 months (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) D. CMV-Associated Gastrointestinal Diseases (off-label) (must meet all):
6. Diagnosis of CMV-associated gastrointestinal disease (e.g., CMV esophagitis, colitis);
7. Prescribed by or in consultation with an infectious disease specialist or gastroenterologist;
8. Age > 16 years;
   4. Member is HIV-positive;
   5. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
9. Dose does not exceed 1,800 mg per day. Approval duration: 42 days (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) E. Post-Transplant CMV Infection (off-label) (must meet all):
10. Diagnosis of CMV infection following hematopoietic stem cell transplant or solid organ transplant (e.g., kidney, lung, heart, liver, pancreas, intestine);
11. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;

12. Valcyte is not prescribed concurrently with Livtencity™; Page 2 of 10

    CLINICAL POLICY Valganciclovir

13. Dose does not exceed 1,800 mg per day. Approval duration: 14 days (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) F. Other diagnoses/indications (must meet 1 or 2):
14. 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 and HIM.PA.33 for health insurance marketplace; 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 and HIM.PA.103 for health insurance marketplace; or
15. 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 and HIM.PA.154 for health insurance marketplace.
    II. Continued Therapy A. CMV Prophylaxis in Heart, Kidney, or Kidney-Pancreas Transplant (must meet all):
    1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Valcyte for a covered indication and has received this medication for at least 30 days;
16. Member meets one of the following (a or b): a. Heart or kidney-pancreas transplant: Member has not received ≥ 6 months of therapy; b. Kidney transplant: Member has not received ≥ 200 days of therapy;
17. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
    
    4. If request is for a dose increase, new dose does not exceed 900 mg per day. Approval duration:
       Heart or kidney-pancreas transplant – Up to 6 months total Kidney transplant – Up to 200 days total (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) B. CMV Retinitis (must meet all):

18. 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 3 of 10

    CLINICAL POLICY Valganciclovir 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);

19. Adherent to antiretroviral therapy (ART) as evidenced by pharmacy claims history;
    3. If member has received ≥ 4 months of therapy, member meets one of the following (a or b): a. CD4 count is < 100 cells/mm3 (within the last 3 months); b. Continuation of therapy is recommended by an ophthalmologist;
20. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
    
    5. If request is for a dose increase, new dose does not exceed 900 mg per day. Approval duration: 3 months (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) C. CMV Prophylaxis in Liver or Lung Transplant (off-label) (must meet all):
21. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Valcyte for a covered indication and has received this medication for at least 30 days;
22. Member meets one of the following (a or b): a. Liver transplant: Member has not received ≥ 6 months of therapy; b. Lung transplant: Member has not received ≥ 12 months of therapy;
23. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
    
    4. If request is for a dose increase, new dose does not exceed 900 mg per day. Approval duration:
       Liver transplant: Up to 6 months total Lung transplant: Up to 12 months total (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) D. CMV-Associated Gastrointestinal Diseases (off-label) (must meet all):
24. 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);

25. Adherent to ART as evidenced by pharmacy claims history;

    3. Member has experienced disease relapse since initial request;
    4. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
    5. If request is for a dose increase, new dose does not exceed 900 mg per day. Approval duration: Duration of request or 3 months (whichever is less) (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) Page 4 of 10

    CLINICAL POLICY Valganciclovir E. Post-Transplant CMV Infection (off-label) (must meet all):

26. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Valcyte for a covered indication and has received this medication for at least 30 days;
27. Member continues to have clinical symptoms and a virologic clearance above a threshold negative value based on laboratory monitoring with CMV quantitative nucleic acid testing (QNAT) or pp65 antigenemia once a week;
28. Member must use generic valganciclovir for the formulation being requested, unless contraindicated or clinically significant adverse effects are experienced;
29. Valcyte is not prescribed concurrently with Livtencity;
    
    5. If request is for a dose increase, new dose does not exceed 1,800 mg per day. Approval duration: Duration of request or 3 months (whichever is less) (For HIM, approve valganciclovir tablets 450 mg only. Refer to HIM.PA.103 for valganciclovir oral solution 50 mg/mL) F. Other diagnoses/indications (must meet 1 or 2):
30. 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 and HIM.PA.33 for health insurance marketplace; 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 and HIM.PA.103 for health insurance marketplace; or

31. 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 and HIM.PA.154 for health insurance marketplace.
    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 and HIM.PA.154 for health insurance marketplace.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AIDS: acquired immunodeficiency syndrome ART: antiretroviral therapy BSA: body surface area CMV: cytomegalovirus CrCl: creatinine clearance FDA: Food and Drug Administration HIV: human immunodeficiency virus QNAT: quantitative nucleic acid testing Page 5 of 10

    CLINICAL POLICY Valganciclovir Appendix B: Therapeutic Alternatives
    Not applicable
    Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity • Boxed warning(s): hematologic toxicity, impairment of fertility, fetal toxicity, mutagenesis, and carcinogenesis
    Appendix D: General Information
    • Based on the 2019 American Society of Transplantation and the 2018 Third International Consensus guidelines for CMV management in solid organ transplantation:
    o 3 to 6 months of prophylaxis therapy is recommended for donor+/recipient- and recipient+ heart transplant, kidney/pancreas transplant, and liver transplant recipients.
    o 6 to 12 months of prophylaxis therapy is recommended for donor+/recipient- and recipient+ lung transplant recipients.
    o CMV disease should be treated with either IV ganciclovir (for severe, life-threatening disease or mild-to-moderate disease) or PO Valcyte (for mild-to-moderate disease). Patients should be treated for a minimum of 2 weeks and until clinical symptoms have resolved and virologic clearance is below a threshold negative value based on weekly laboratory monitoring with CMV QNAT or pp65 antigenemia. After completion of full-dose antiviral treatment, secondary prophylaxis intended to prevent CMV relapse is not recommended as a routine practice. • Based on the results of the IMPACT study, Valcyte prophylaxis for 200 days in kidney transplant patients resulted in a reduction in CMV disease. At 2 years post-transplant, CMV disease occurred in significantly less patients in the 200- vs. the 100-day group: 21.3% vs. 38.7%, respectively (p < 0.001). • Although Valcyte is not FDA approved for the prevention of CMV disease in liver transplant patients, consensus treatment guidelines support the use of Valcyte in this transplant type. The FDA has cautioned against valganciclovir prophylaxis in liver recipients due to high rate of tissue-invasive disease compared to oral ganciclovir.
    • Data supporting the use of Valcyte for lung transplant patients come from Finlen et al, who concluded that 12 months of Valcyte prophylaxis compared with 3 months provided a protective benefit with a CMV incidence of 12% vs 55% respectively (HR 0.13, CI: 0.03-0.61, p = 0.009). In another randomized clinical trial by Palmer et al, extending the duration of Valcyte prophylaxis from 3 months to 12 months decreased the incidence of CMV disease from 64% to 10% (p < 0.001). • Per CDC guidelines for the treatment of CMV retinitis, Valcyte may be used in combination with ganciclovir intraocular implant for patients with immediate sight- threatening lesions (adjacent to the optic nerve or fovea). • Chronic maintenance therapy is not routinely recommended for CMV gastrointestinal disease, unless there is concurrent retinitis or relapses have occurred. • The safety and efficacy of Valcyte for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection. In 2010, the FDA added an upper limit to pediatric dosing Page 6 of 10

    CLINICAL POLICY Valganciclovir calculation to prevent Valcyte overdosing in children with low body weight, surface area and below normal serum creatinine.
    V. Dosage and Administration
    Indication Prevention of CMV disease in heart or kidney-pancreas transplant patients Prevention of CMV disease in kidney transplant patients Treatment of CMV retinitis Prevention of CMV disease in liver transplantation† Prevention of CMV disease in lung transplantation† Treatment of CMV esophagitis† or colitis† Treatment of post-transplant CMV infection† Prevention of CMV disease in kidney transplant patients 4 months to 16 years of age Prevention of CMV disease in heart transplant patients 1 month to 16 years of age Dosing Regimen Adult Dosage 900 mg (two 450 mg tablets) PO QD within 10 days of transplantation until 100 days post-transplantation 900 mg (two 450 mg tablets) PO QD within 10 days of transplantation until 200 days post-transplantation Induction: 900 mg (two 450 mg tablets) PO BID for 14-21 days Maintenance: 900 mg (two 450 mg tablets) PO QD 900 mg (two 450 mg tablets) PO QD within 10 days of transplantation 900 mg (two 450 mg tablets) PO QD within 10 days of transplantation Induction: 900 mg (two 450 mg tablets) PO BID for 21-42 days
    Maintenance (may be considered in patients with relapse): 900 mg (two 450 mg tablets) PO QD
    900 mg PO BID for at least 14 days Pediatric Dosage Calculated dose in mg (7 x BSA x CrCl) PO QD within 10 days of transplantation until 200 days post- transplantation
    Calculated dose in mg (7 x BSA x CrCl) PO QD within 10 days of transplantation until 100 days post- transplantation Calculated dose in mg (7 x BSA x CrCl) PO BID for at least 14 days Maximum Dose 900 mg/day 900 mg/day Induction: 1,800 mg/day;
    Maintenance: 900 mg/day 900 mg/day 900 mg/day Induction: 1,800 mg/day;
    Maintenance: 900 mg/day 1,800 mg/day 900 mg/day 900 mg/day 1,800 mg/day Treatment of post-transplant CMV infection† Calculated using a modified Schwartz formula † Off-label indication VI. Product Availability
    • Oral solution: 50 mg/mL • Tablet: 450 mg Page 7 of 10

    CLINICAL POLICY Valganciclovir VII.