Regulatory Status FDA approved indications: Valctye is a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor indicated for: (1)

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1 Federal Employee Program 1310 G Street, N.W. Washington, D.C Fax Subject: Valcyte Page: 1 of 6 Last Review Date: September 18, 2015 Valcyte Description Valcyte (valganciclovir) Background Valcyte (valganciclovir) is an orally administered antiviral prodrug with no antiviral activity until converted in the body to ganciclovir (1). Ganciclovir is used in the treatment of Cytomegalovirus (CMV) by interfering with DNA synthesis. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with Valcyte. The bioavailability of ganciclovir for Valcyte is significantly higher than ganciclovir capsules (2,3). Therefore, Valcyte tablets cannot be substituted for ganciclovir capsules on a mg-per-mg basis (1,4). In adult patients, Valcyte (valganciclovir) tablets are indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Valcyte tablets are also indicated for the prevention of CMV disease in kidney, heart, or kidneypancreas transplant patients at high risk (Donor CMV seropositive/recipient CMV seronegative [D+/R-]). Adult patients should use the Valcyte tablets, not the Valcyte oral solution (1). Regulatory Status FDA approved indications: Valctye is a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor indicated for: (1) Adult Patients 1. Treatment of Cytomegalovirus (CMV) Retinitis: Valcyte tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).

2 Subject: Valcyte Page: 2 of 6 2. Prevention of CMV Disease: Valcyte tablets are indicated 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 1. Prevention of CMV Disease: Valcyte for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant patients (4 months to 16 years of age) at high risk. Off-label Uses: (6-12). 1. Treatment of cytomegalovirus (CMV) disease in symptomatic patients 2. Prevention of CMV infection in post-hematopoietic stem cell transplant (HSCT) 3. Prevention of CMV infection in post solid organ transplant (including liver or lung) In pediatric patients, both the tablets and oral solution of Valcyte (valganciclovir hydrochloride) are indicated for the prevention of CMV disease in kidney or heart transplant patients (4 months to 16 years of age) who are at high risk. Cytomegalovirus (CMV) infections are among the most common infections that occur following solid organ transplantation. Organ transplant recipients at highest risk of CMV infection are those who are seronegative before transplantation and receive an organ from a seropositive donor (a combination commonly referred to as donor-positive/ recipient-negative [D + /R - ]); in these patients, latent CMV can be transmitted with the organ and subsequently reactivate, causing de novo or primary infection. The incidence of CMV disease in D - /R - transplantations is <5% (7). Valcyte has a boxed warning of hematologic toxicity, carcinogenicity, teratogenicity, and impairment of fertility. Clinical toxicity of Valcyte, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia (1). Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have been observed with the use of Valcyte or ganciclovir (1). Valcyte should not be administered if the absolute neutrophil count is <500 cells/µl, the platelet count is <25,000/µL, or the hemoglobin is <8 g/dl (1). Use with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during

3 Subject: Valcyte Page: 3 of 6 treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug (1). Advise women of childbearing potential to use effective contraception during treatment and for at least 30 days following treatment with Valcyte. Advise men to practice barrier contraception during and for at least 90 days following treatment (1). Acute renal failure may occur in elderly patients with or without reduced renal function, patients receiving concomitant nephrotoxic drugs, or patients without adequate hydration (1). Monitor CBC with differential, platelets, ophthalmic, and renal function. Patients must maintain adequate hydration (1). Related policies Policy This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Valcyte may be considered medically necessary for the treatment of Cytomegalovirus (CMV) disease in symptomatic patients, or for the prevention of CMV disease in patients who are post solid organ transplant (including heart, liver, lung, kidney, or kidney-pancreas), post hematopoietic cell transplant (HCT), or under treatment for HIV. Valcyte is considered investigational in patients who are CMV sero-negative recipients of a solid organ transplant from a CMV sero-negative donor and in patients with an absolute neutrophil count (ANC) less than 500 cells/µl, a platelet count less than 25,000/µL, or a hemoglobin less than 8 g/dl. Prior-Approval Requirements Patients with an HIV diagnosis (one or more anti-retroviral claims in the last 12 months) are exempt from this PA requirement. Diagnoses Patient must have ONE of the following: 1. Treatment of Cytomegalovirus (CMV) disease in symptomatic patients

4 Subject: Valcyte Page: 4 of 6 2. Prevention (either prophylaxis or preemptive therapy) of CMV disease in patients who are: AND ONE of the following 1. Post solid organ transplant (including heart, liver, lung, kidney, or kidneypancreas) 2. Post hematopoietic stem cell transplant (HSCT) AND ALL of the following: 1. Absolute neutrophil count (ANC) > 500 cells/µl 2. Platelet count > 25,000/µL 3. Hemoglobin > 8 g/dl AND NONE of the following: 1. CMV sero-negative recipient of solid organ transplant from a CMV sero-negative donor (R-/D-) Prior Approval Renewal Requirements Same as above Policy Guidelines Pre - PA Allowance None Prior - Approval Limits Duration 12 months Prior Approval Renewal Limits Duration 12 months Rationale Summary Valcyte (valganciclovir) is an orally administered antiviral prodrug with no antiviral activity until converted in vivo to ganciclovir, and subsequently to the active ganciclovir triphosphate.

5 Subject: Valcyte Page: 5 of 6 Ganciclovir triphosphate has in vitro and in vivo inhibitory activity against cytomegalovirus (CMV). In adult patients, Valcyte (valganciclovir) tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Valcyte tablets are also indicated for the prevention of CMV disease in kidney, heart, or kidney-pancreas transplant patients at high risk. Appropriate off-label indications include the treatment of symptomatic CMV infection and the prevention of CMV disease in high-risk lung and liver transplant patients. Prior authorization is required to ensure the safe, clinically appropriate and cost effective use of Valcyte while maintaining optimal therapeutic outcomes. References 1. Valcyte. [Prescribing information]. South San Francisco, CA. Genentech USA, Inc. April Brown F, Banken L, Saywell K et al. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet. 1999; 37: [PubMed ]. 3. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMVseropositive subjects. J Clin Pharmacol. 1999; 39: [IDIS ] [PubMed ] 4. US Food and Drug Administration (FDA). FDA drug safety communication: New dosing recommendations to prevent potential Valcyte (valganciclovir) overdose in pediatric transplant patients Sep 15. From FDA website. 5. Martin DF, Sierra-Madero J, Walmsley S et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med. 2002; 346: [IDIS ] [PubMed ] 6. Personal Communication, Gerald Medoff, MD, Infectious Diseases, Washington University Hospital, March 1, 2012, for treatment of symptomatic CMV infection, and off-label use posttransplant by recipients of lung and liver transplants. 7. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89: Humar A, Snydman D, and the AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S78 S86 9. Humar A, Snydman D, and the AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S78 S86

6 Subject: Valcyte Page: 6 of Snydman DR, Limaye AP, Potena L, Zamora MR. Update and Review: State-of-the-art management of cytomegalovirus infection and disease following thoracic organ transplantation. 11. Transplantation Proceedings 2011; 43, S1 S Fayek SA, Mantipisitkul W, Rasetto F, et al. Vanganciclovir is an effective prophylaxis for cytomegalovirus disease in liver transplant patients. HPB 2010;12: Policy History Date Action Reason June 2012 March 2013 June 2014 September 2015 New Addition Off-label: Added lung and liver to post solid organ transplant Annual editorial review Annual editorial review Annual editorial review and reference update Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on September 18, 2015 and is effective October 1, Deborah M. Smith, M.D., MPH