ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the labeling:Hematologic Toxicity [see Warnings and Precautions (5.1)].Acute Renal Failure [see Warnings and Precautions (5.2)].Impairment of Fertility [see Warnings and Precautions (5.3)].Fetal Toxicity [see Warnings and Precautions (5.4)].Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with VALCYTE tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with VALCYTE for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. Hematologic Toxicity [see Warnings and Precautions (5.1)].. Acute Renal Failure [see Warnings and Precautions (5.2)].. Impairment of Fertility [see Warnings and Precautions (5.3)].. Fetal Toxicity [see Warnings and Precautions (5.4)].. Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].. Adult patients: Most common adverse reactions and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. (6.1)Pediatric patients: Most common adverse reactions and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact 1-866-946-3684 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adult patients: Most common adverse reactions and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. (6.1). Pediatric patients: Most common adverse reactions and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.Valganciclovir, prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse reactions known to be associated with ganciclovir usage can therefore be expected to occur with VALCYTE. Adverse Reactions in Adults:. Treatment of CMV Retinitis in AIDS Patients: In clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions reported by patients receiving VALCYTE tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), and headache (9%, 5%). The incidence of adverse reactions was similar between the group who received VALCYTE tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/uL) were 11% for patients receiving VALCYTE tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.Adverse reactions and laboratory abnormalities are available for 370 patients who received maintenance therapy with VALCYTE tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received VALCYTE tablets for more than nine months (maximum duration was 36 months). Table and Table show pooled selected adverse reactions and abnormal laboratory values from these patients.Table Pooled Selected Adverse Reactions Reported in greater than or equal to 5% of Patients who Received VALCYTE Tablets Maintenance Therapy for CMV RetinitisPatients with CMV RetinitisAdverse Reactions according to Body SystemVALCYTE Tablets(N=370)%Gastrointestinal system Diarrhea41 Nausea30 Vomiting21 Abdominal pain15General disorders and administrative site conditions Pyrexia31Nervous system disorders Headache22 Insomnia16 Neuropathy peripheral9 Paresthesia8Eye disorders Retinal detachment15Table Pooled Selected Laboratory Abnormalities Reported in Patients Who Received VALCYTE Tablets Maintenance Therapy for the Treatment of CMV RetinitisPatients with CMV RetinitisLaboratory AbnormalitiesVALCYTE Tablets(N=370)%Neutropenia: ANC/uL 50019 500 < 75017 750 < 100017Anemia: Hemoglobin g/dL 6.57 6.5 < 8.013 8.0 < 9.516Thrombocytopenia: Platelets/uL 250004 25000 < 500006 50000 < 10000022Serum Creatinine: mg/dL 2.53 1.5 2.512. Prevention of CMV Disease in Solid Organ Transplant Patients:Table shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received VALCYTE tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse reactions were of mild or moderate intensity.Table Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients From Study of Solid Organ Transplant PatientsAdverse ReactionsVALCYTE Tablets(N=244)%Oral Ganciclovir(N=126)%Gastrointestinal disordersDiarrhea3029Nausea2323Vomiting1614Nervous system disordersTremors2825Headache2227Insomnia2016General disorders and administration site conditionsPyrexia1314Table shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either valganciclovir once daily starting within 10 days post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily until Day 200 post-transplant. The overall safety profile of VALCYTE did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients.Table Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients from Study of Kidney Transplant PatientsAdverse ReactionsVALCYTE TabletsDay 100 Post-transplant(N=164)%VALCYTE TabletsDay 200 Post-transplant(N=156)%Gastrointestinal disordersDiarrhea2631Nausea1111Vomiting36Nervous system disordersTremors1217Headache106Insomnia76General disorders and administration site conditionsPyrexia129Table and Table show selected laboratory abnormalities reported with VALCYTE tablets in two trials in solid organ transplant patients.Table Selected Laboratory Abnormalities Reported in Study of Adult Solid Organ Transplant Patients Laboratory AbnormalitiesVALCYTE Tablets(N=244)%Ganciclovir Capsules(N=126)%Neutropenia: ANC/uL 50053 500 < 75032 750 < 100052Anemia: Hemoglobin g/dL 6.512 6.5 < 8.057 8.0 < 9.53125Thrombocytopenia: Platelets/uL 2500002 25000 < 5000013 50000 < 1000001821Serum Creatinine: mg/dL 2.51421 1.5 2.54547Table Selected Laboratory Abnormalities Reported in Study of Adult Kidney Transplant Patients Laboratory AbnormalitiesVALCYTE TabletsDay 100 Post-transplant(N=164)%VALCYTE TabletsDay 200 Post-transplant(N=156)%Neutropenia: ANC/uL 500910 500 < 75066 750 < 100075Anemia: Hemoglobin g/dL 6.501 6.5 < 8.051 8.0 < 9.51715Thrombocytopenia: Platelets/uL 2500000 25000 < 5000010 50000 < 10000073Serum Creatinine: mg/dL 2.51714 1.5 2.55048. Other adverse drug reactions from VALCYTE in clinical trials in CMV retinitis and solid organ transplant patientsOther adverse drug reactions with VALCYTE in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in at least 5% of patients are listed below. Eye disorders: retinal detachment, eye painGastrointestinal disorders: dyspepsia, constipation, abdominal distention, mouth ulcerationGeneral disorders and administration site conditions: fatigue, pain, malaise, asthenia, chills, peripheral edemaHepatobiliary disorders: hepatic function abnormalInfections and infestations: candida infections including oral candidiasis, upper respiratory tract infection, influenza, urinary tract infection, pharyngitis/nasopharyngitis, postoperative wound infectionInjury, poisoning, and procedural complications: postoperative complications, wound secretionMetabolic and nutrition disorders: decreased appetite, hyperkalemia, hypophosphatemia, weight decreased Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasmsNervous system disorders: insomnia, neuropathy peripheral, dizziness Psychiatric disorders: depression, anxietyRenal and urinary disorders: renal impairment, creatinine clearance renal decreased, blood creatinine increased, hematuria Respiratory, thoracic and mediastinal disorders: cough, dyspneaSkin and subcutaneous tissues disorders: dermatitis, night sweats, pruritus Vascular disorders: hypotensionOther adverse reactions with VALCYTE in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in less than 5% of patients are listed below. Blood and lymphatic disorders: febrile neutropenia, pancytopenia, bone marrow failure (including aplastic anemia)Cardiovascular disorders: arrhythmiaEar and labyrinth disorders: deafnessEye disorders: macular edemaGastrointestinal disorders: pancreatitisHemorrhage: potentially life-threatening bleeding associated with thrombocytopeniaImmune system disorders: hypersensitivityInfections and infestations: cellulitis, sepsisInjury, poisoning, and procedural complications: postoperative pain, wound dehiscenceInvestigations: aspartate aminotransferase increased, alanine aminotransferase increasedMusculoskeletal and connective tissue disorders: limb pain Nervous system disorders: seizure, dysguesia (taste disturbance)Psychiatric disorders: confusional state, agitation, psychotic disorder, hallucinationsRenal and urinary disorders: renal failure. Adverse Reactions in Pediatric Patients:VALCYTE for oral solution and tablets have been studied in 179 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged weeks to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged to 34 days), with duration of ganciclovir exposure ranging from to 200 days [see Use in Specific Populations (8.4), Clinical Studies (14.2)].. Prevention of CMV Disease in Pediatric Solid Organ Transplant Patients: The most frequently reported adverse reactions (greater than 10% of patients), regardless of seriousness, in pediatric solid organ transplant patients taking VALCYTE until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation and nausea. The most frequently reported adverse reactions (greater than 10% of patients) in pediatric kidney transplant patients treated with valganciclovir until Day 200 post-transplant were upper respiratory tract infection, urinary tract infection, diarrhea, leukopenia, neutropenia, headache, abdominal pain, tremor, pyrexia, anemia, blood creatinine increased, vomiting, and hematuria. In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse reactions, and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. Neutropenia was reported at higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.The overall safety profile of VALCYTE was similar with the extension of prophylaxis until Day 200 post-transplant in high risk pediatric kidney transplant patients. However, the incidence of severe neutropenia (ANC 500/uL) was higher in pediatric kidney transplant patients treated with VALCYTE until Day 200 (17/57, 30%) compared to pediatric kidney transplant patients treated until Day 100 (3/63, 5%). There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated 100 or 200 days with VALCYTE.. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of VALCYTE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. As VALCYTE is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir. -Anaphylactic reaction-Agranulocytosis-GranulocytopeniaIn general, the adverse reactions reported during the postmarketing use of VALCYTE were similar to those identified during the clinical trials. -Anaphylactic reaction. -Agranulocytosis. -Granulocytopenia.

BOXED WARNING SECTION.

WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS. Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE [see Warnings and Precautions (5.1)]. Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)]. Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)]. Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans [see Warnings and Precautions (5.5)]. Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE [see Warnings and Precautions (5.1)]. Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)]. Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)]. Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans [see Warnings and Precautions (5.5)]. WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESISSee full prescribing information for complete boxed warning.Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE. (5.1) Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. (5.3)Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans. (5.4) Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans. (5.5). Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE. (5.1) Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. (5.3). Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans. (5.4) Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans. (5.5).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies have not been conducted with VALCYTE. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is potential carcinogen. Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose, there was significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered potential carcinogen in humans. Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay. Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see Warnings and Precautions (5.3)]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7x the mean drug exposure in humans following the dose of mg per kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. These effects were reversible at lower doses but irreversible at higher doses. It is considered likely that ganciclovir (and valganciclovir) could cause temporary or permanent inhibition of human spermatogenesis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Valganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].. 12.3 Pharmacokinetics. Valganciclovir is prodrug of ganciclovir. Valganciclovir Cmax and AUC are approximately 1% and 3% of those of ganciclovir, respectively.. Pharmacokinetics in Adults: The pharmacokinetics of ganciclovir after administration of valganciclovir tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients (Table 10).Table 10Ganciclovir PharmacokineticsData were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis. in Healthy Volunteers and HIV-positive/CMV-positive Adults Administered VALCYTE Tablets 900 mg Once Daily with FoodPK parameterNValue (Mean +- SD)AUC0-24h (mcgh/mL)5729.1 +- 9.7Cmax (mcg/mL)585.61 +- 1.52Absolute oral bioavailability (%)3259.4 +- 6.1Elimination half-life (hr)734.08 +- 0.76Renal clearance (mL/min/kg)203.21 +- 0.75(1 study, n=20)The systemic ganciclovir exposures attained following administration of 900 mg VALCYTE tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11). Table 11Ganciclovir Pharmacokinetics in Solid Organ Transplant Recipients Administered VALCYTE Tablets 900 mg Once Daily with FoodParameterValue (Mean +- SD)Heart Transplant Recipients(N=17)Liver Transplant Recipients(N=75)Kidney Transplant RecipientsIncludes kidney-pancreas (N=68)AUC0-24h (mcgh/mL)40.2 +- 11.846.0 +- 16.148.2 +- 14.6Cmax (mcg/mL)4.9 +- 1.15.4 +- 1.55.3 +- 1.5Elimination half-life (hr)6.58 +- 1.506.18 +- 1.426.77 +- 1.25The pharmacokinetic parameters of ganciclovir following 200 days of VALCYTE administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received VALCYTE for 100 days.. Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of VALCYTE are provided in Table 12.Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with VALCYTEValganciclovirGanciclovirAbsorptionTmax (h)median (min-max) (fed conditions)2.181.7h to 3.0hFood effect (high fat meal/fasting): PK parameter ratio and 90% confidence intervalSteady state ganciclovir PK was assessed after administration of VALCYTE tablets (875 mg once daily) with high fat meal containing approximately 600 total calories (31.1 fat, 51.6 carbohydrates and 22.2 protein) to 16 HIV-positive subjects. Cmax: 1.14 (0.95, 1.36)AUC: 1.30 (1.07, 1.51) Tmax: <->Distribution% Bound to human plasma proteins (ex vivo)Unknown1-2% over 0.5- 51 mcg/mLCerebrospinal fluid penetrationUnknownYesMetabolismHydrolyzed by intestinal and liver esterasesNo significant metabolismEliminationDose proportionalityAUC was dose proportional under fed conditions across valganciclovir dose range of 450 to 2625 mgMajor route of elimination Metabolism to ganciclovirGlomerular filtration and active tubular secretiont1/2 (h)See Tables 10 and 11 Of dose excreted in urineUnknown% Of dose excreted in fecesUnknown. Specific Populations: Renal Impairment: The pharmacokinetics of ganciclovir from single oral dose of 900 mg VALCYTE tablets were evaluated in 24 otherwise healthy individuals with renal impairment. Decreased renal function results in decreased clearance of ganciclovir and increased terminal half-life (Table 13).Table 13Pharmacokinetics of Ganciclovir from Single Oral Dose of 900 mg VALCYTE TabletsEstimated Creatinine ClearanceCreatinine clearance calculated from 24-hour urine collection. (mL/min)NApparent Clearance(mL/min)Mean +- SDAUClast (mcgh/mL)Mean +- SDHalf-life(hours)Mean +- SD51-706249 +- 9949.5 +- 22.44.85 +- 1.421-506136 +- 6491.9 +- 43.910.2 +- 4.411-20645 +- 11223 +- 4621.8 +- 5.2<= 10612.8 +- 8366 +- 6667.5 +- 34Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following VALCYTE administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use VALCYTE tablets because the daily dose of VALCYTE tablets required for these patients is less than 450 mg [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged months to 16 years, and in 16 pediatric heart transplant patients less than months of age. In these studies, patients received oral doses of valganciclovir (either VALCYTE for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)]. In studies using the pediatric valganciclovir dosing algorithm, the pharmacokinetics of ganciclovir were similar across organ types and age ranges (Table 14). Relative to adult transplant patients (Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults. Table 14Ganciclovir Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patients Administered VALCYTEOrganPK Parameter mean (SD)Age Group 4 months4 months to <= years> to 12 years>= 12 yearsN=number of patients, NA=not applicableHeart(N=26)N14Ages ranged from 26 to 124 days. 624AUC0-24h (mcgh/mL)66.3 (20.5)55.4 (22.8)59.6 (21.0)60.6 (25.0)Cmax (mcg/mL)10.8 (3.30)8.2 (2.5)12.5 (1.2)9.5 (3.3)t1/2 (h)3.5 (0.87)3.8 (1.7)2.8 (0.9)4.9 (0.8)Kidney(N=31)NNA21019AUC0-24h (mcgh/mL)67.6 (13.0)55.9 (12.1)47.8 (12.4)Cmax (mcg/mL)10.4 (0.4)8.7 (2.1)7.7 (2.1)t1/2 (h)4.5 (1.5)4.8 (1.0)6.0 (1.3)Liver(N=17)NNA962AUC0-24h (mcgh/mL)69.9 (37.0)59.4 (8.1)35.4 (2.8)Cmax (mcg/mL)11.9 (3.7)9.5 (2.3)5.5 (1.1)t1/2 (h)2.8 (1.5)3.8 (0.7)4.4 (0.2). Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of VALCYTE in elderly patients have not been established. Drug Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for VALCYTE [see Drug Interactions (7)]. Table 15 and Table 16 provide listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.Table 15Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic ParametersCoadministered DrugGanciclovir DosageNGanciclovir Pharmacokinetic (PK) ParameterMycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No effect on ganciclovir PK parameters observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg every hours12No effect on ganciclovir PK parameters observedDidanosine 200 mg every 12 hours simultaneously administered with ganciclovir5 mg/kg IV twice daily 11No effect on ganciclovir PK parameters observed5 mg/kg IV once daily 11No effect on ganciclovir PK parameters observedProbenecid 500 mg every hours1000 mg every hours10AUC 53 +- 91% (range: -14% to 299%)Ganciclovir renal clearance 22 +- 20% (range: -54% to -4%)Table 16Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered DrugCoadministered DrugGanciclovir DosageNCoadministered Drug Pharmacokinetic (PK) ParameterOral cyclosporine at therapeutic doses5 mg/kg infused over hour every 12 hours93In retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.Mycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No PK interaction observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg every hours12No effect on trimethoprim PK parameters observedDidanosine 200 mg every 12 hours5 mg/kg IV twice daily11AUC0-12 70 +- 40% (range: 3% to 121%)Cmax49 +- 48% (range: -28% to 125%)Didanosine 200 mg every 12 hours5 mg/kg IV once daily11AUC0-12 50 +- 26%(range: 22% to 110%)Cmax 36 +- 36%(range: -27% to 94%). 12.4 Microbiology. Mechanism of Action: Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is synthetic analogue of 2-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54 by ganciclovir triphosphate.. Antiviral Activity: The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC50), vary greatly depending upon number of factors including the assay used. Thus, the reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 uM (0.02 to 5.75 mcg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was to uM (35%), 1.1 to uM (20%), 2.1 to uM (27%), 3.1 to uM (13%), 4.1 to uM (5%), less than uM (less than 1%). Ganciclovir inhibits mammalian cell proliferation (CC50) in cell culture at higher concentrations ranging from 40 to greater than 1,000 uM (10.21 to greater than 250 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value 2.7 to 12 uM (0.69 to 3.06 mcg/mL)]. Viral Resistance:. Cell culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L). In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with valganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, and C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 17 Table 17Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or ProphylaxisNote: Many additional pathways to ganciclovir resistance likely existpUL97F342Y, K359E/Q, L405P, A440V, M460I/V/T/L, V466G/M, C480F, C518Y, H520Q, P521L, del 590-593, A591D/V, C592F/G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G/Y, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, I610T, A613VpUL54E315D, N408D/K/S, F412C/L/S, D413A/E/N, L501F/I, T503I, K513E/N/R, D515E, L516W, I521T, P522A/L/S, V526L, C539G, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, L773V, V781I, V787E/L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987GThe presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) [see Clinical Studies (14.1)]. Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance-associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D; 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.. Cross-Resistance: Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 18 Substitutions at amino acid positions pUL97 340-400 have been found to confer resistance to ganciclovir. Resistance data based on assays that do not include this region should be interpreted cautiously.Table 18Summary of pUL54 Amino Acid Substitutions with Cross-Resistance between Ganciclovir, Cidofovir, and/or FoscarnetCross-resistant to cidofovirD301N, N408D/K, N410K, F412C/L/S/V, D413E/N, P488R, L501I, T503I, K513E/N, L516R/W, I521T, P522S/A, V526L, C539G/R, L545S/W, Q578H, D588N, I726T/V, E756K, L733V, V787E, V812L, T813S, A834P, G841A, del 981-982, A987GCross-resistant to foscarnetF412C, Q578H/L, D588N, V715A/M, E756K, L733V, V776M, V781I, V787E/L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adult Patients. Induction Therapy of CMV Retinitis: In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either VALCYTE tablets (900 mg twice daily for 21 days, then 900 mg once daily for days) or with intravenous ganciclovir solution (5 mg per kg twice daily for 21 days, then mg per kg once daily for days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and Week was the primary outcome measurement of the 3-week induction therapy. Table 19 provides the outcomes at weeks.Table 19Week Masked Review of Retinal Photographs in CMV Retinitis Study Intravenous GanciclovirVALCYTE TabletsDetermination of CMV retinitis progression at Week 4N=80N=80Progressor77Non-progressor6364Death21Discontinuations due to Adverse Events12Failed to return11CMV not confirmed at baseline or no interpretable baseline photos65. Maintenance Therapy of CMV Retinitis: No comparative clinical data are available on the efficacy of VALCYTE tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label VALCYTE tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg VALCYTE tablets once daily and mg per kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following VALCYTE tablets administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration. Therefore, use of VALCYTE tablets as maintenance therapy is supported by plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis. Prevention of CMV Disease in Heart, Kidney, Kidney-Pancreas, or Liver Transplantation: double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (D+/R-). Patients were randomized (2 VALCYTE: oral ganciclovir) to receive either VALCYTE tablets (900 mg once daily) or oral ganciclovir (1000 mg three times day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first months post-transplant was similar between the VALCYTE tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the VALCYTE group compared with the ganciclovir group. These results are summarized in Table 20.Mortality at six months was 3.7% (9/244) in the VALCYTE group and 1.6% (2/126) in the oral ganciclovir group.Table 20Percentage of Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome by Organ Type: Endpoint Committee, Month ITT PopulationCMV DiseaseNumber of patients with CMV disease Number of patients with tissue-invasive CMV disease or CMV syndrome Tissue-Invasive CMV DiseaseCMV SyndromeCMV syndrome was defined as evidence of CMV viremia accompanied with fever greater than or equal to 38C on two or more occasions separated by at least 24 hours within 7-day period and one or more of the following: malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases OrganVGCV(N=239)GCV(N=125)VGCV(N=239)GCV(N=125)VGCV(N=239)GCV(N=125)GCV oral ganciclovir; VGCV valganciclovirLiver (n=177)19%(22/118)12%(7/59)14%(16/118)3%(2/59)5%(6/118)8%(5/59)Kidney (n=120)6%(5/81)23%(9/39)1%(1/81)5%(2/39)5%(4/81)18%(7/39)Heart(n=56)6%(2/35)10%(2/21)0%(0/35)5%(1/21)6%(2/35)5%(1/21)Kidney/Pancreas(n=11)0%(0/5)17%(1/6)0%(0/5)17%(1/6)0%(0/5)0%(0/6). Prevention of CMV Disease in Kidney Transplantation: double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending VALCYTE CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive VALCYTE tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with VALCYTE until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 21 Table 21Percentage of Kidney Transplant Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome, 12 Month ITT PopulationCMV DiseaseNumber of patients with CMV disease Number of patients with tissue-invasive CMV disease or CMV syndrome Tissue-Invasive CMV DiseaseCMV SyndromeCMV syndrome was defined as evidence of CMV viremia accompanied with at least one of the following: fever (greater than or equal to 38C), severe malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases 100 DaysVGCV(N=163) 200 DaysVGCV(N=155) 100 DaysVGCV(N=163)200 DaysVGCV(N=155)100 DaysVGCV(N=163)200 DaysVGCV(N=155)VGCV valganciclovir.Cases36.8%(60/163)16.8%(26/155)1.8%(3/163)Two patients in the 100 day group had both tissue-invasive CMV disease and CMV syndrome; however, these patients are counted as having only tissue-invasive CMV disease. 0.6%(1/155)35. 0%(57/163)16.1%(25/155)The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.. 14.2Pediatric Patients. Prevention of CMV in Pediatric Heart, Kidney, or Liver Transplantation: Sixty-three children, months to 16 years of age, who had solid organ transplant (kidney 33, liver 17, heart 12, and kidney/liver 1) and were at risk for developing CMV disease, were enrolled in an open-label, safety, and pharmacokinetic study of oral VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until maximum of 100 days post-transplant. The daily doses of VALCYTE were calculated at each study visit based on body surface area and modified creatinine clearance [see Dosage and Administration (2.3)]. The pharmacokinetics of ganciclovir were similar across organ transplant types and age ranges. The mean daily ganciclovir exposures in pediatric patients were somewhat increased relative to those observed in adult solid organ transplant patients receiving VALCYTE 900 mg once daily, but were within the range considered safe and effective in adults [see Clinical Pharmacology (12.3)]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first six months post-transplantation.. Prevention of CMV in Pediatric Kidney Transplantation: Fifty-seven children, to 16 years of age, who had renal transplant and were at risk for developing CMV disease, were enrolled in an open-label tolerability study of oral VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until maximum of 200 days post-transplant. The daily doses of VALCYTE were calculated at each study visit based on body surface area and modified creatinine clearance [see Dosage and Administration (2.3)]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first 12 months post-transplantation.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. VALCYTE is contraindicated in patients who have had demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)]. Hypersensitivity to valganciclovir or ganciclovir. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. VALCYTE contains valganciclovir hydrochloride (valganciclovir HCl), hydrochloride salt of the L-valyl ester of ganciclovir that exists as mixture of two diastereomers. Ganciclovir is synthetic guanine derivative active against CMV.VALCYTE is available as 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. The film-coat applied to the tablets contains Opadry Pink(R).VALCYTE is also available as powder for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of VALCYTE for oral solution are sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring.Valganciclovir HCl is white to off-white crystalline powder with molecular formula of C14H22N6O5HCl and molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is polar hydrophilic compound with solubility of 70 mg/mL in water at 25C at pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir HCl is 7.6.The chemical structure of valganciclovir HCl is:All doses in this insert are specified in terms of valganciclovir.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adult Dosage (2.2)Treatment of CMV retinitis Induction: 900 mg (two 450 mg tablets) twice day for 21 daysMaintenance: 900 mg (two 450 mg tablets) once dayPrevention of CMV disease in heart or kidney-pancreas transplant patients900 mg (two 450 mg tablets) once day within 10 days of transplantation until 100 days post-transplantationPrevention of CMV disease in kidney transplant patients900 mg (two 450 mg tablets) once day within 10 days of transplantation until 200 days post-transplantationPediatric Dosage (2.3)Prevention of CMV disease in kidney transplant patients months to 16 years of ageDose once day within 10 days of transplantation until 200 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using modified Schwartz formula in children) Prevention of CMV disease in heart transplant patients month to 16 years of ageDose once day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using modified Schwartz formula in children)VALCYTE for oral solution and tablets should be taken with food. (2.1, 12.3)VALCYTE tablets should not be broken or crushed. (2.6)Adult patients should use VALCYTE tablets, not VALCYTE for oral solution. (2.1)Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis dose recommendation cannot be given. (2.5, 8.6, 12.3). VALCYTE for oral solution and tablets should be taken with food. (2.1, 12.3). VALCYTE tablets should not be broken or crushed. (2.6). Adult patients should use VALCYTE tablets, not VALCYTE for oral solution. (2.1). Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis dose recommendation cannot be given. (2.5, 8.6, 12.3). 2.1General Dosing Information. Adult patients should use VALCYTE tablets, not VALCYTE for oral solution.VALCYTE for oral solution and tablets should be taken with food [see Clinical Pharmacology (12.3)].VALCYTE for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].. Adult patients should use VALCYTE tablets, not VALCYTE for oral solution.. VALCYTE for oral solution and tablets should be taken with food [see Clinical Pharmacology (12.3)].. VALCYTE for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].. 2.2Recommended Dosage in Adult Patients with Normal Renal Function. For dosage recommendations in adult patients with renal impairment [see Dosage and Administration (2.5)]. Treatment of CMV Retinitis:Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice day for 21 days.Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day.. Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice day for 21 days.. Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day.. Prevention of CMV Disease: For adult patients who have received heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day starting within 10 days of transplantation until 100 days post-transplantation.For adult patients who have received kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day starting within 10 days of transplantation until 200 days post-transplantation.. For adult patients who have received heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day starting within 10 days of transplantation until 100 days post-transplantation.. For adult patients who have received kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once day starting within 10 days of transplantation until 200 days post-transplantation.. 2.3Recommended Dosage in Pediatric Patients. Prevention of CMV Disease in Pediatric Kidney Transplant Patients: For pediatric kidney transplant patients months to 16 years of age, the recommended once daily mg dose (7 BSA CrCl) should start within 10 days of post-transplantation until 200 days post-transplantation.. Prevention of CMV Disease in Pediatric Heart Transplant Patients: For pediatric heart transplant patients month to 16 years of age, the recommended once daily mg dose (7 BSA CrCl) should start within 10 days of transplantation until 100 days post-transplantation.The recommended once daily dosage of VALCYTE is based on body surface area (BSA) and creatinine clearance (CrCl) derived from modified Schwartz formula, and is calculated using the equation below:Pediatric Dose (mg) 7 BSA CrCl (calculated using modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2, then maximum value of 150 mL/min/1.73m2 should be used in the equation. The values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.Schwartz Creatinine Clearance (mL min 1.73m 2) k Height (cm)Serum Creatinine (mg dL)Table k Values According to Pediatric Patient Age valuePediatric Patient Age0.33Infants less than year of age with low birth weight for gestational age0.45Infants less than year of age with birth weight appropriate for gestational age0.45Children aged to less than years0.55Boys aged to less than 13 yearsGirls aged to less than 16 years0.7Boys aged 13 to 16 yearsMonitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. The oral dispenser is graduated in 0.5 mL increments. 50 mg dose is equivalent to mL. If the calculated dose exceeds 900 mg, maximum dose of 900 mg should be administered. VALCYTE for oral solution is the preferred formulation since it provides the ability to administer dose calculated according to the formula above; however, VALCYTE tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. Before prescribing VALCYTE tablets, pediatric patients should be assessed for the ability to swallow tablets.. Equation. 2.4Preparation of VALCYTE for Oral Solution Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Prior to dispensing to the patient, VALCYTE for oral solution must be prepared by the pharmacist as follows [see How Supplied/Storage and Handling (16)]:Measure 91 mL of purified water in graduated cylinder.Shake the VALCYTE bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about minute. Add the remainder of water and shake the closed bottle well for about minute. This prepared solution contains 50 mg of valganciclovir free base per mL.Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.Store constituted oral solution under refrigeration at 2C to 8C (36F to 46F) for no longer than 49 days. Do not freeze. Write the discard date of the constituted oral solution on the bottle label.The patient package insert, which includes the dosing instructions for patients, and oral dispensers should be dispensed to the patient [see Patient Counseling Information (17)].. Measure 91 mL of purified water in graduated cylinder.. Shake the VALCYTE bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about minute. Add the remainder of water and shake the closed bottle well for about minute. This prepared solution contains 50 mg of valganciclovir free base per mL.. Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.. Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.. Store constituted oral solution under refrigeration at 2C to 8C (36F to 46F) for no longer than 49 days. Do not freeze. Write the discard date of the constituted oral solution on the bottle label.. 2.5Dosage Recommendation for Adult Patients with Renal Impairment. Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), dose recommendation for VALCYTE cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Table 2Dosage Recommendations for Adult Patients with Impaired Renal FunctionVALCYTE 450 mg TabletsCrCl (mL/min)Induction DoseMaintenance/Prevention Dose>= 60900 mg twice daily900 mg once daily40 59450 mg twice daily450 mg once daily25 39450 mg once daily450 mg every days10 24450 mg every days450 mg twice weekly< 10(on hemodialysis)not recommendednot recommendedAn estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:For males (140 age [years]) (body weight [kg])(72) (serum creatinine [mg/dL])For females 0.85 male value Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is component in the calculation [see Dosage and Administration (2.3)].. 2.6Handling and Disposal. Caution should be exercised in the handling of VALCYTE tablets and VALCYTE for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, the powder for oral solution, and the constituted oral solution [see Warnings and Precautions (5.4, 5.5)]. Avoid direct contact with broken or crushed tablets, the powder for oral solution, and the constituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.Handle and dispose VALCYTE according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity).2.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. VALCYTE tablets: 450 mg, pink, film-coated convex oval tablets with VGC on one side and 450 on the other side.VALCYTE for oral solution: 50 mg per mL, supplied as white to slightly yellow powder for constitution, forming colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution.. VALCYTE tablets: 450 mg, pink, film-coated convex oval tablets with VGC on one side and 450 on the other side.. VALCYTE for oral solution: 50 mg per mL, supplied as white to slightly yellow powder for constitution, forming colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution.. Tablets: 450 mg. (3) Oral Solution: 50 mg per mL. (3). Tablets: 450 mg. (3) Oral Solution: 50 mg per mL. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for VALCYTE. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of VALCYTE and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.Table 9Established and Other Potentially Significant Drug Interactions with GanciclovirName of the Concomitant DrugChange in the Concentration of Ganciclovir or Concomitant DrugClinical CommentImipenem-cilastatinUnknownCoadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.Cyclosporine or amphotericin BUnknownMonitor renal function when VALCYTE is coadministered with cyclosporine or amphotericin because of potential increase in serum creatinine [see Warnings and Precautions (5.2)]. Mycophenolate mofetil (MMF)<-> Ganciclovir (in patients with normal renal function)<-> MMF (in patients with normal renal function)Based on increased risk, patients should be monitored for hematological and renal toxicity.Other drugs associated with myelosuppression or nephrotoxicity (e.g., adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine, and zidovudine)UnknownBecause of potential for higher toxicity, coadministration with VALCYTE should be considered only if the potential benefits are judged to outweigh the risks. Didanosine<-> Ganciclovir DidanosinePatients should be closely monitored for didanosine toxicity (e.g., pancreatitis) Probenecid GanciclovirVALCYTE dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. (7)Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7)Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. (7)Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. (7)Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). (7)Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. (7). Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. (7). Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7). Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. (7). Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. (7). Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). (7). Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. (7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingFemales of reproductive potential should undergo pregnancy testing before initiation of VALCYTE [see Use in Specific Populations (8.1)].. Contraception. FemalesBecause of the mutagenic and teratogenic potential of VALCYTE, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE [see Dosage and Administration (2.6), Warnings and Precautions (5.4, 5.5), Nonclinical Toxicology (13.1)].. MalesBecause of its mutagenic potential, males should be advised to use condoms during and for at least 90 days following, treatment with VALCYTE [see Dosage and Administration (2.6), Warnings and Precautions (5.3, 5.5), Nonclinical Toxicology (13.1)]. InfertilityVALCYTE at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)]. Data. Human DataIn small, open-label, non-randomized clinical study, adult male renal transplant patients receiving VALCYTE for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after VALCYTE discontinuation. Among 24 evaluable patients in the VALCYTE group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the VALCYTE group the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the VALCYTE group and by 43 million/mL in the untreated group).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Studies of VALCYTE for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because renal clearance decreases with age, VALCYTE should be administered with consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. VALCYTE tablets: Supplied as 450 mg, pink, convex oval tablets with VGC on one side and 450 on the other side. Each tablet contains 450 mg valganciclovir. VALCYTE is supplied in bottles of 60 tablets (NDC 61269-480-60).. Store VALCYTE tablets at 20C to 25C (68F to 77F); excursions are permitted to 15C to 30C (59F to 86F) [see USP controlled room temperature].. VALCYTE for oral solution: Supplied as white to slightly yellow powder blend for constitution, forming colorless to brownish-yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Each bottle can deliver up to total of 88 mL of solution. Each bottle is supplied with bottle adapter and oral dispensers (NDC 61269-485-10).Prior to dispensing to the patient, VALCYTE for oral solution must be prepared by the pharmacist [see Dosage and Administration (2.4)]. Store dry powder at 20C to 25C (68F to 77F); excursions are permitted to 15C to 30C (59F to 86F) [see USP controlled room temperature].Store constituted solution under refrigeration at 2C to 8C (36F to 46F) for no longer than 49 days. Do not freeze.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. VALCYTE is deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for:Adult Patients (1.1)Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).Prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk.Pediatric Patients (1.2)Prevention of CMV disease in kidney and heart transplant patients at high risk.. Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).. Prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk.. Prevention of CMV disease in kidney and heart transplant patients at high risk.. 1.1Adult Patients. Treatment of Cytomegalovirus (CMV) Retinitis: VALCYTE is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].. Prevention of CMV Disease: VALCYTE is indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].. 1.2Pediatric Patients. Prevention of CMV Disease: VALCYTE is indicated for the 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 [see Clinical Studies (14.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Serious Adverse ReactionsInform patients that VALCYTE may cause granulocytopenia (neutropenia), anemia, thrombocytopenia and elevated creatinine levels and that dose modification or discontinuation of dosing may be required. Complete blood counts, platelet counts, and creatinine levels should be monitored frequently during treatment [see Warnings and Precautions (5.1)]. Pregnancy and ContraceptionInform females of reproductive potential that VALCYTE causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with VALCYTE. Similarly, advise males to use condoms during and for at least 90 days following treatment with VALCYTE [see Use in Specific Populations (8.1, 8.3)].. CarcinogenicityAdvise patients that VALCYTE is considered potential carcinogen [see Nonclinical Toxicity (13.1)]. LactationAdvise mothers not to breast-feed if they are receiving VALCYTE because of the potential for hematologic toxicity and cancer in nursing infants, and because HIV can be passed to the baby in breast milk [see Use in Specific Populations (8.2)]. InfertilityAdvise patients that VALCYTE may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)].. Impairment of Cognitive Ability Inform patients that tasks requiring alertness may be affected including the patients ability to drive and operate machinery as seizures, dizziness, and/or confusion have been reported with the use of VALCYTE [see Adverse Reactions (6.1)]. Use in Patients with CMV RetinitisInform patients that VALCYTE is not cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have ophthalmologic follow-up examinations at minimum of every to weeks while being treated with VALCYTE. Some patients will require more frequent follow-up.. AdministrationInform adult patients that they should use VALCYTE tablets, not VALCYTE for oral solution [see Dosage and Administration (2.1)]. Inform patients to take VALCYTE with food to maximize bioavailability.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseVALCYTE (Val-site)(valganciclovir)for oral solution. Be sure that you read, and that you understand and follow these instructions carefully to ensure proper dosing of the oral solution.Important: Avoid contact with your skin or eyes. If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.Do not use VALCYTE for oral solution after the discard date on the bottle.Always use the oral dispenser provided to give or take dose of VALCYTE for oral solution.Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to give or take dose of VALCYTE for oral solution.Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.To take dose of VALCYTE for oral solution, you will need the bottle of medicine and an oral dispenser provided with the medicine (see Figure 1). Your pharmacist inserts the bottle adapter in the VALCYTE for oral solution bottle.Figure 1Step 1: With the child-resistant cap on the bottle, shake the bottle well for about seconds before each use.Step 2: Open the bottle by pressing downward firmly on the child-resistant cap and turning it counter-clockwise. Do not throw away the child-resistant cap. Step 3: Check the dose in milliliters (mL) as prescribed by your healthcare provider. Find this number on the oral dispenser.Step 4: Push the plunger down toward the tip of the oral dispenser.Step 5: With the bottle in an upright position, insert the oral dispenser into the bottle adapter opening until firmly in place.Step 6: Carefully turn the bottle upside down with the oral dispenser in place. Pull the plunger to withdraw the prescribed dose. If you see air bubbles in the oral dispenser, fully push in the plunger so that the oral solution flows back into the bottle. Then withdraw your prescribed dose of VALCYTE for oral solution.Step 7: Leave the oral dispenser in the bottle adapter and turn the bottle to an upright position. Slowly remove the oral dispenser from the bottle adapter.Step 8:Give or take the dose of VALCYTE for oral solution.Place the tip of the oral dispenser in the mouth.Slowly push down the oral dispenser plunger until the oral dispenser is empty.Step 9: Put the child-resistant cap back on the bottle. Return the bottle back to the refrigerator.Step 10: Rinse the oral dispenser with tap water after each use.Remove the plunger from the oral dispenser barrel by pulling the plunger all the way out of the barrel.Rinse the oral dispenser barrel and plunger with water and let them air dry.When the oral dispenser barrel and plunger are dry, put the plunger back into the oral dispenser barrel for the next use.Do not throw away the oral dispenser.How should store VALCYTE for oral solutionStore solution in the refrigerator at 36F to 46F (2C to 8C) for no longer than 49 days.Do not freeze.This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.VALCYTE is registered trademark of CHEPLAPHARM Arzneimittel GmbH.Distributed by: H2-Pharma, LLC Montgomery, AL 36117, USALicensed by: CHEPLAPHARM Arzneimittel GmbH Ziegelhof 24, 17489 Greifswald, GermanyRevised: 04/2023For more information call 1-866-946-3684.(C) 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.. Avoid contact with your skin or eyes. If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.. Do not use VALCYTE for oral solution after the discard date on the bottle.. Always use the oral dispenser provided to give or take dose of VALCYTE for oral solution.. Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to give or take dose of VALCYTE for oral solution.. Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.. Place the tip of the oral dispenser in the mouth.. Slowly push down the oral dispenser plunger until the oral dispenser is empty.. Remove the plunger from the oral dispenser barrel by pulling the plunger all the way out of the barrel.. Rinse the oral dispenser barrel and plunger with water and let them air dry.. When the oral dispenser barrel and plunger are dry, put the plunger back into the oral dispenser barrel for the next use.. Store solution in the refrigerator at 36F to 46F (2C to 8C) for no longer than 49 days.. Do not freeze.. Figure 1. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. Animal data indicate that ganciclovir is excreted in the milk of lactating rats. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Advise nursing mothers that breastfeeding is not recommended during treatment with VALCYTE because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV [see Boxed Warning, Warnings and Precautions (5.1, 5.3, 5.4, 5.5), Nonclinical Toxicology (13.1)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Valganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action: Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is synthetic analogue of 2-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54 by ganciclovir triphosphate.. Antiviral Activity: The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC50), vary greatly depending upon number of factors including the assay used. Thus, the reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 uM (0.02 to 5.75 mcg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was to uM (35%), 1.1 to uM (20%), 2.1 to uM (27%), 3.1 to uM (13%), 4.1 to uM (5%), less than uM (less than 1%). Ganciclovir inhibits mammalian cell proliferation (CC50) in cell culture at higher concentrations ranging from 40 to greater than 1,000 uM (10.21 to greater than 250 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value 2.7 to 12 uM (0.69 to 3.06 mcg/mL)]. Viral Resistance:. Cell culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L). In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with valganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, and C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 17 Table 17Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or ProphylaxisNote: Many additional pathways to ganciclovir resistance likely existpUL97F342Y, K359E/Q, L405P, A440V, M460I/V/T/L, V466G/M, C480F, C518Y, H520Q, P521L, del 590-593, A591D/V, C592F/G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G/Y, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, I610T, A613VpUL54E315D, N408D/K/S, F412C/L/S, D413A/E/N, L501F/I, T503I, K513E/N/R, D515E, L516W, I521T, P522A/L/S, V526L, C539G, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, L773V, V781I, V787E/L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987GThe presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) [see Clinical Studies (14.1)]. Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance-associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D; 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.. Cross-Resistance: Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 18 Substitutions at amino acid positions pUL97 340-400 have been found to confer resistance to ganciclovir. Resistance data based on assays that do not include this region should be interpreted cautiously.Table 18Summary of pUL54 Amino Acid Substitutions with Cross-Resistance between Ganciclovir, Cidofovir, and/or FoscarnetCross-resistant to cidofovirD301N, N408D/K, N410K, F412C/L/S/V, D413E/N, P488R, L501I, T503I, K513E/N, L516R/W, I521T, P522S/A, V526L, C539G/R, L545S/W, Q578H, D588N, I726T/V, E756K, L733V, V787E, V812L, T813S, A834P, G841A, del 981-982, A987GCross-resistant to foscarnetF412C, Q578H/L, D588N, V715A/M, E756K, L733V, V776M, V781I, V787E/L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies have not been conducted with VALCYTE. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is potential carcinogen. Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose, there was significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered potential carcinogen in humans. Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay. Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see Warnings and Precautions (5.3)]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7x the mean drug exposure in humans following the dose of mg per kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. These effects were reversible at lower doses but irreversible at higher doses. It is considered likely that ganciclovir (and valganciclovir) could cause temporary or permanent inhibition of human spermatogenesis.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Experience with VALCYTE Tablets: An overdose of VALCYTE could possibly result in increased renal toxicity [see Dosage and Administration (2.5), Use in Specific Populations (8.6)]. Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of VALCYTE [see Clinical Pharmacology (12.3)]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Reports of adverse reactions after overdoses with valganciclovir, some with fatal outcomes, have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events: Hematological toxicity: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopeniaHepatotoxicity: hepatitis, liver function disorderRenal toxicity: worsening of hematuria in patient with pre-existing renal impairment, acute kidney injury, elevated creatinineGastrointestinal toxicity: abdominal pain, diarrhea, vomitingNeurotoxicity: generalized tremor, seizure.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 450 mg Bottle Carton. NDC 61269-480-60Valcyte(R) (valganciclovir) tablets450 mgDO NOT BREAK OR CRUSH TABLETSCAUTION: Strict adherence to dosage recommendations is essential to avoid overdose.60 tabletsRx onlyCHEPLAPHARM. PRINCIPAL DISPLAY PANEL 450 mg Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. VALCYTE for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients months to 16 years of age and in pediatric heart transplant patients month to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)]. The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric kidney transplant patients months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients months to 16 years of age. Study was safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). VALCYTE was administered once daily within 10 days of transplantation for maximum of 100 days post-transplantation. Study was safety and tolerability study where VALCYTE was administered once daily within 10 days of transplantation for maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients month to 16 years of age is based on two studies (Study described above and Study 3) and was supported by previous demonstration of efficacy in adult patients [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Study was pharmacokinetic and safety study of VALCYTE in pediatric heart transplant patients less than months of age who received single dose of VALCYTE oral solution on each of two consecutive days. physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than month of age. However, due to uncertainty in model predictions for neonates, VALCYTE is not indicated for prophylaxis in this age group.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 months of age, in heart transplant patients less than month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.A pharmacokinetic and pharmacodynamic evaluation of VALCYTE for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for weeks with combination of intravenous ganciclovir mg per kg twice daily or VALCYTE for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than days to months of age, dose of 16 mg per kg twice daily of VALCYTE for oral solution provided ganciclovir systemic exposures (median AUC0-12h=23.6 [range 16.8-35.5] mcgh/mL; n=6) comparable to those obtained in infants up to months of age from 6 mg per kg dose of intravenous ganciclovir twice daily (AUC0-12h=25.3 [range 2.4-89.7] mcgh/mL; n=18) or to the ganciclovir systemic exposures obtained in adults from 900 mg dose of VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Valganciclovir is prodrug of ganciclovir. Valganciclovir Cmax and AUC are approximately 1% and 3% of those of ganciclovir, respectively.. Pharmacokinetics in Adults: The pharmacokinetics of ganciclovir after administration of valganciclovir tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients (Table 10).Table 10Ganciclovir PharmacokineticsData were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis. in Healthy Volunteers and HIV-positive/CMV-positive Adults Administered VALCYTE Tablets 900 mg Once Daily with FoodPK parameterNValue (Mean +- SD)AUC0-24h (mcgh/mL)5729.1 +- 9.7Cmax (mcg/mL)585.61 +- 1.52Absolute oral bioavailability (%)3259.4 +- 6.1Elimination half-life (hr)734.08 +- 0.76Renal clearance (mL/min/kg)203.21 +- 0.75(1 study, n=20)The systemic ganciclovir exposures attained following administration of 900 mg VALCYTE tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11). Table 11Ganciclovir Pharmacokinetics in Solid Organ Transplant Recipients Administered VALCYTE Tablets 900 mg Once Daily with FoodParameterValue (Mean +- SD)Heart Transplant Recipients(N=17)Liver Transplant Recipients(N=75)Kidney Transplant RecipientsIncludes kidney-pancreas (N=68)AUC0-24h (mcgh/mL)40.2 +- 11.846.0 +- 16.148.2 +- 14.6Cmax (mcg/mL)4.9 +- 1.15.4 +- 1.55.3 +- 1.5Elimination half-life (hr)6.58 +- 1.506.18 +- 1.426.77 +- 1.25The pharmacokinetic parameters of ganciclovir following 200 days of VALCYTE administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received VALCYTE for 100 days.. Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of VALCYTE are provided in Table 12.Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with VALCYTEValganciclovirGanciclovirAbsorptionTmax (h)median (min-max) (fed conditions)2.181.7h to 3.0hFood effect (high fat meal/fasting): PK parameter ratio and 90% confidence intervalSteady state ganciclovir PK was assessed after administration of VALCYTE tablets (875 mg once daily) with high fat meal containing approximately 600 total calories (31.1 fat, 51.6 carbohydrates and 22.2 protein) to 16 HIV-positive subjects. Cmax: 1.14 (0.95, 1.36)AUC: 1.30 (1.07, 1.51) Tmax: <->Distribution% Bound to human plasma proteins (ex vivo)Unknown1-2% over 0.5- 51 mcg/mLCerebrospinal fluid penetrationUnknownYesMetabolismHydrolyzed by intestinal and liver esterasesNo significant metabolismEliminationDose proportionalityAUC was dose proportional under fed conditions across valganciclovir dose range of 450 to 2625 mgMajor route of elimination Metabolism to ganciclovirGlomerular filtration and active tubular secretiont1/2 (h)See Tables 10 and 11 Of dose excreted in urineUnknown% Of dose excreted in fecesUnknown. Specific Populations: Renal Impairment: The pharmacokinetics of ganciclovir from single oral dose of 900 mg VALCYTE tablets were evaluated in 24 otherwise healthy individuals with renal impairment. Decreased renal function results in decreased clearance of ganciclovir and increased terminal half-life (Table 13).Table 13Pharmacokinetics of Ganciclovir from Single Oral Dose of 900 mg VALCYTE TabletsEstimated Creatinine ClearanceCreatinine clearance calculated from 24-hour urine collection. (mL/min)NApparent Clearance(mL/min)Mean +- SDAUClast (mcgh/mL)Mean +- SDHalf-life(hours)Mean +- SD51-706249 +- 9949.5 +- 22.44.85 +- 1.421-506136 +- 6491.9 +- 43.910.2 +- 4.411-20645 +- 11223 +- 4621.8 +- 5.2<= 10612.8 +- 8366 +- 6667.5 +- 34Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following VALCYTE administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use VALCYTE tablets because the daily dose of VALCYTE tablets required for these patients is less than 450 mg [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged months to 16 years, and in 16 pediatric heart transplant patients less than months of age. In these studies, patients received oral doses of valganciclovir (either VALCYTE for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)]. In studies using the pediatric valganciclovir dosing algorithm, the pharmacokinetics of ganciclovir were similar across organ types and age ranges (Table 14). Relative to adult transplant patients (Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults. Table 14Ganciclovir Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patients Administered VALCYTEOrganPK Parameter mean (SD)Age Group 4 months4 months to <= years> to 12 years>= 12 yearsN=number of patients, NA=not applicableHeart(N=26)N14Ages ranged from 26 to 124 days. 624AUC0-24h (mcgh/mL)66.3 (20.5)55.4 (22.8)59.6 (21.0)60.6 (25.0)Cmax (mcg/mL)10.8 (3.30)8.2 (2.5)12.5 (1.2)9.5 (3.3)t1/2 (h)3.5 (0.87)3.8 (1.7)2.8 (0.9)4.9 (0.8)Kidney(N=31)NNA21019AUC0-24h (mcgh/mL)67.6 (13.0)55.9 (12.1)47.8 (12.4)Cmax (mcg/mL)10.4 (0.4)8.7 (2.1)7.7 (2.1)t1/2 (h)4.5 (1.5)4.8 (1.0)6.0 (1.3)Liver(N=17)NNA962AUC0-24h (mcgh/mL)69.9 (37.0)59.4 (8.1)35.4 (2.8)Cmax (mcg/mL)11.9 (3.7)9.5 (2.3)5.5 (1.1)t1/2 (h)2.8 (1.5)3.8 (0.7)4.4 (0.2). Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of VALCYTE in elderly patients have not been established. Drug Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for VALCYTE [see Drug Interactions (7)]. Table 15 and Table 16 provide listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.Table 15Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic ParametersCoadministered DrugGanciclovir DosageNGanciclovir Pharmacokinetic (PK) ParameterMycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No effect on ganciclovir PK parameters observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg every hours12No effect on ganciclovir PK parameters observedDidanosine 200 mg every 12 hours simultaneously administered with ganciclovir5 mg/kg IV twice daily 11No effect on ganciclovir PK parameters observed5 mg/kg IV once daily 11No effect on ganciclovir PK parameters observedProbenecid 500 mg every hours1000 mg every hours10AUC 53 +- 91% (range: -14% to 299%)Ganciclovir renal clearance 22 +- 20% (range: -54% to -4%)Table 16Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered DrugCoadministered DrugGanciclovir DosageNCoadministered Drug Pharmacokinetic (PK) ParameterOral cyclosporine at therapeutic doses5 mg/kg infused over hour every 12 hours93In retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.Mycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No PK interaction observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg every hours12No effect on trimethoprim PK parameters observedDidanosine 200 mg every 12 hours5 mg/kg IV twice daily11AUC0-12 70 +- 40% (range: 3% to 121%)Cmax49 +- 48% (range: -28% to 125%)Didanosine 200 mg every 12 hours5 mg/kg IV once daily11AUC0-12 50 +- 26%(range: 22% to 110%)Cmax 36 +- 36%(range: -27% to 94%).

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, VALCYTE is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of VALCYTE or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)]. Clinical Considerations Disease-associated maternal and/or embryo/fetal riskMost maternal CMV infections are asymptomatic or they may be associated with self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in these infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.. Data. Animal DataDoses resulting in two-times the human exposure of ganciclovir (based on the human AUC following single intravenous infusion of mg per kg of ganciclovir) resulted in maternal and embryo-fetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryo-fetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryo-fetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7 times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach.Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over concentration range of to 10 mg/mL.

REFERENCES SECTION.

15 REFERENCES. 1. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. of Ped 1986: 109(4): 698-707. 2. NIOSH [2014]. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor TH, MacKenzie BA, DeBord DG, Trout DB, OCallaghan JP, Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONVALCYTE (Val-site) (valganciclovir)tabletsVALCYTE (Val-site)(valganciclovir)for oral solutionWhat is the most important information should know about VALCYTEVALCYTE can cause serious side effects, including: Blood and bone marrow problems. VALCYTE can affect the bone marrow lowering the amount of your white blood cells, red blood cells, and platelets and may cause serious and life-threatening problems.Kidney failure. Kidney failure may happen in people who are elderly, people who take VALCYTE with certain other medicines, or people who are not adequately hydrated.Fertility problems. VALCYTE may lower sperm count in males and cause fertility problems. VALCYTE may also cause fertility problems in women. Talk to your healthcare provider if this is concern for you.Birth defects. VALCYTE causes birth defects in animals. It is not known if VALCYTE causes birth defects in people. If you are female who can become pregnant, you should use effective birth control during treatment with VALCYTE and for at least 30 days after treatment. If you are pregnant, talk to your healthcare provider before starting treatment with VALCYTE. If you are female who can become pregnant, you should have pregnancy test done before starting VALCYTE. Tell your healthcare provider right away if you become pregnant during treatment with VALCYTE.Males should use condoms during treatment with VALCYTE, and for at least 90 days after treatment, if their female sexual partner can become pregnant. Talk to your healthcare provider if you have questions about birth control. Cancer. VALCYTE causes cancer in animals and may potentially cause cancer in people.Your healthcare provider will do regular blood tests during treatment with VALCYTE to check you for side effects. Your healthcare provider may change your dose or stop treatment with VALCYTE if you have serious side effects. What is VALCYTEVALCYTE is prescription antiviral medicine.In adults, VALCYTE tablets are used:to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS). When CMV virus infects the eyes, it is called CMV retinitis. If CMV retinitis is not treated, it can cause blindness.to prevent CMV disease in people who have received kidney, heart, or kidney-pancreas transplant and who have high risk for getting CMV disease.VALCYTE does not cure CMV retinitis. You may still get retinitis or worsening of retinitis during or after treatment with VALCYTE. It is important to stay under healthcare providers care and have your eyes checked at least every to weeks during treatment with VALCYTE. In children, VALCYTE tablets or oral solution are used: to prevent CMV disease in children months to 16 years of age who have received kidney transplant and have high risk for getting CMV disease.to prevent CMV disease in children month to 16 years of age who have received heart transplant and have high risk for getting CMV disease.It is not known if VALCTYE is safe and effective in children for prevention of CMV disease in liver transplant, in kidney transplant in infants less than months of age, in heart transplant in infants less than month of age, in children with AIDS who have CMV retinitis, and in infants with congenital CMV infection.Do not take VALCYTE if you have had serious allergic reaction to valganciclovir, ganciclovir or any of the ingredients of VALCYTE. See the end of this leaflet for list of the ingredients in VALCYTE.Before you take VALCYTE, tell your healthcare provider about all of your medical conditions, including if you:have low blood cell countshave kidney problemsare receiving hemodialysisare receiving radiation treatmentare pregnant or plan to become pregnant. See What is the most important information should know about VALCYTE are breastfeeding or plan to breastfeed. It is not known if VALCYTE passes into your breast milk. You should not breastfeed if you take VALCYTE.You should not breastfeed if you have Human Immunodeficiency Virus (HIV-1) because of the risk of passing HIV-1 to your baby.Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins and herbal supplements. VALCYTE and other medicines may affect each other and cause serious side effects. Keep list of your medicines to show your healthcare provider and pharmacist.You can ask your healthcare provider or pharmacist for list of medicines that interact with VALCYTE.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take VALCYTE with other medicines.How should take VALCYTETake VALCYTE exactly as your healthcare provider tells you. Your dose of VALCYTE will depend on your medical condition.Adults should only take VALCYTE tablets. Children may take either VALCYTE tablets or oral solution.Take VALCYTE with food.Do not break or crush VALCYTE tablets. Avoid contact with your skin or eyes. If you come in contact with the contents of the tablet or oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.If your child is prescribed VALCYTE for oral solution, your pharmacist will give you oral dosing dispensers to measure your childs dose of VALCYTE for oral solution. To be sure you receive the prescribed dose, it is important to use the dispenser provided to you. See the detailed Instructions for Use below for information about how to take VALCYTE for oral solution. Ask your pharmacist if you have any questions. If you lose or damage your oral dispensers and cannot use them, contact your pharmacist.If you take too much VALCYTE, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid during treatment with VALCYTEVALCYTE can cause seizures, dizziness, and confusion. You should not drive car or operate machinery until you know how VALCYTE affects you.What are the possible side effects of VALCYTEVALCYTE may cause serious side effects, including:See What is the most important information should know about VALCYTEThe most common side effects of VALCYTE in adults include: diarrheafeverfatiguenauseashaky movements (tremors)low white cell, red cell and platelet cell counts in blood testsheadachesleeplessnessurinary tract infectionvomitingThe most common side effects of VALCYTE in children include:diarrheafeverupper respiratory tract infectionurinary tract infectionvomitinglow white blood cell counts in blood testsheadacheThese are not all the possible side effects of VALCYTE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store VALCYTEStore VALCYTE tablets at room temperature between 68F to 77F (20C to 25C).Store VALCYTE for oral solution in the refrigerator between 36F to 46F (2C to 8C), for no longer than 49 days.Do not freeze.Do not keep VALCYTE that is out of date or that you no longer need.Keep VALCYTE and all medicines out of the reach of children.General information about the safe and effective use of VALCYTE.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use VALCYTE for condition for which it was not prescribed. Do not give VALCYTE to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VALCYTE that is written for health professionals.What are the ingredients in VALCYTE Active ingredient: valganciclovir hydrochloride Inactive ingredients for tablets: microcrystalline cellulose, povidone K-30, crospovidone, and stearic acid. The film-coating applied to the tablets contains Opadry Pink(R). Inactive ingredients for oral solution: sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring.VALCYTE is registered trademark of CHEPLAPHARM Arzneimittel GmbH.Distributed by: H2-Pharma, LLC Montgomery, AL 36117, USALicensed by: CHEPLAPHARM Arzneimittel GmbH Ziegelhof 24, 17489 Greifswald, GermanyRevised: 04/2023For more information call 1-866-946-3684.(C) 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.. Blood and bone marrow problems. VALCYTE can affect the bone marrow lowering the amount of your white blood cells, red blood cells, and platelets and may cause serious and life-threatening problems.. Kidney failure. Kidney failure may happen in people who are elderly, people who take VALCYTE with certain other medicines, or people who are not adequately hydrated.. Fertility problems. VALCYTE may lower sperm count in males and cause fertility problems. VALCYTE may also cause fertility problems in women. Talk to your healthcare provider if this is concern for you.. Birth defects. VALCYTE causes birth defects in animals. It is not known if VALCYTE causes birth defects in people. If you are female who can become pregnant, you should use effective birth control during treatment with VALCYTE and for at least 30 days after treatment. If you are pregnant, talk to your healthcare provider before starting treatment with VALCYTE. If you are female who can become pregnant, you should have pregnancy test done before starting VALCYTE. Tell your healthcare provider right away if you become pregnant during treatment with VALCYTE.Males should use condoms during treatment with VALCYTE, and for at least 90 days after treatment, if their female sexual partner can become pregnant. Talk to your healthcare provider if you have questions about birth control. Tell your healthcare provider right away if you become pregnant during treatment with VALCYTE.. Males should use condoms during treatment with VALCYTE, and for at least 90 days after treatment, if their female sexual partner can become pregnant. Talk to your healthcare provider if you have questions about birth control.. Cancer. VALCYTE causes cancer in animals and may potentially cause cancer in people.. to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS). When CMV virus infects the eyes, it is called CMV retinitis. If CMV retinitis is not treated, it can cause blindness.. to prevent CMV disease in people who have received kidney, heart, or kidney-pancreas transplant and who have high risk for getting CMV disease.. to prevent CMV disease in children months to 16 years of age who have received kidney transplant and have high risk for getting CMV disease.. to prevent CMV disease in children month to 16 years of age who have received heart transplant and have high risk for getting CMV disease.. have low blood cell counts. have kidney problems. are receiving hemodialysis. are receiving radiation treatment. are pregnant or plan to become pregnant. See What is the most important information should know about VALCYTE are breastfeeding or plan to breastfeed. It is not known if VALCYTE passes into your breast milk. You should not breastfeed if you take VALCYTE.You should not breastfeed if you have Human Immunodeficiency Virus (HIV-1) because of the risk of passing HIV-1 to your baby.Talk to your healthcare provider about the best way to feed your baby. You should not breastfeed if you have Human Immunodeficiency Virus (HIV-1) because of the risk of passing HIV-1 to your baby.. Talk to your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with VALCYTE.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take VALCYTE with other medicines.. Take VALCYTE exactly as your healthcare provider tells you. Your dose of VALCYTE will depend on your medical condition.. Adults should only take VALCYTE tablets. Children may take either VALCYTE tablets or oral solution.. Take VALCYTE with food.. Do not break or crush VALCYTE tablets. Avoid contact with your skin or eyes. If you come in contact with the contents of the tablet or oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.. If your child is prescribed VALCYTE for oral solution, your pharmacist will give you oral dosing dispensers to measure your childs dose of VALCYTE for oral solution. To be sure you receive the prescribed dose, it is important to use the dispenser provided to you. See the detailed Instructions for Use below for information about how to take VALCYTE for oral solution. Ask your pharmacist if you have any questions. If you lose or damage your oral dispensers and cannot use them, contact your pharmacist.. If you take too much VALCYTE, call your healthcare provider or go to the nearest hospital emergency room right away.. diarrhea. fever. fatigue. nausea. shaky movements (tremors). low white cell, red cell and platelet cell counts in blood tests. headache. sleeplessness. urinary tract infection. vomiting. diarrhea. fever. upper respiratory tract infection. urinary tract infection. vomiting. low white blood cell counts in blood tests. headache. Store VALCYTE tablets at room temperature between 68F to 77F (20C to 25C).. Store VALCYTE for oral solution in the refrigerator between 36F to 46F (2C to 8C), for no longer than 49 days.. Do not freeze.. Do not keep VALCYTE that is out of date or that you no longer need.

SPL UNCLASSIFIED SECTION.

1.1Adult Patients. Treatment of Cytomegalovirus (CMV) Retinitis: VALCYTE is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].. Prevention of CMV Disease: VALCYTE is indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].

STORAGE AND HANDLING SECTION.

Store VALCYTE tablets at 20C to 25C (68F to 77F); excursions are permitted to 15C to 30C (59F to 86F) [see USP controlled room temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended with use of VALCYTE. (8.2). Lactation: Breastfeeding is not recommended with use of VALCYTE. (8.2). 8.1 Pregnancy. Risk Summary After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, VALCYTE is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of VALCYTE or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)]. Clinical Considerations Disease-associated maternal and/or embryo/fetal riskMost maternal CMV infections are asymptomatic or they may be associated with self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in these infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.. Data. Animal DataDoses resulting in two-times the human exposure of ganciclovir (based on the human AUC following single intravenous infusion of mg per kg of ganciclovir) resulted in maternal and embryo-fetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryo-fetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryo-fetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7 times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach.Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over concentration range of to 10 mg/mL.. 8.2 Lactation. Risk SummaryNo data are available regarding the presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. Animal data indicate that ganciclovir is excreted in the milk of lactating rats. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Advise nursing mothers that breastfeeding is not recommended during treatment with VALCYTE because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV [see Boxed Warning, Warnings and Precautions (5.1, 5.3, 5.4, 5.5), Nonclinical Toxicology (13.1)].. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingFemales of reproductive potential should undergo pregnancy testing before initiation of VALCYTE [see Use in Specific Populations (8.1)].. Contraception. FemalesBecause of the mutagenic and teratogenic potential of VALCYTE, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE [see Dosage and Administration (2.6), Warnings and Precautions (5.4, 5.5), Nonclinical Toxicology (13.1)].. MalesBecause of its mutagenic potential, males should be advised to use condoms during and for at least 90 days following, treatment with VALCYTE [see Dosage and Administration (2.6), Warnings and Precautions (5.3, 5.5), Nonclinical Toxicology (13.1)]. InfertilityVALCYTE at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)]. Data. Human DataIn small, open-label, non-randomized clinical study, adult male renal transplant patients receiving VALCYTE for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after VALCYTE discontinuation. Among 24 evaluable patients in the VALCYTE group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the VALCYTE group the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the VALCYTE group and by 43 million/mL in the untreated group).. 8.4 Pediatric Use. VALCYTE for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients months to 16 years of age and in pediatric heart transplant patients month to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)]. The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric kidney transplant patients months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients months to 16 years of age. Study was safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). VALCYTE was administered once daily within 10 days of transplantation for maximum of 100 days post-transplantation. Study was safety and tolerability study where VALCYTE was administered once daily within 10 days of transplantation for maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients month to 16 years of age is based on two studies (Study described above and Study 3) and was supported by previous demonstration of efficacy in adult patients [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Study was pharmacokinetic and safety study of VALCYTE in pediatric heart transplant patients less than months of age who received single dose of VALCYTE oral solution on each of two consecutive days. physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than month of age. However, due to uncertainty in model predictions for neonates, VALCYTE is not indicated for prophylaxis in this age group.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 months of age, in heart transplant patients less than month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.A pharmacokinetic and pharmacodynamic evaluation of VALCYTE for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for weeks with combination of intravenous ganciclovir mg per kg twice daily or VALCYTE for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than days to months of age, dose of 16 mg per kg twice daily of VALCYTE for oral solution provided ganciclovir systemic exposures (median AUC0-12h=23.6 [range 16.8-35.5] mcgh/mL; n=6) comparable to those obtained in infants up to months of age from 6 mg per kg dose of intravenous ganciclovir twice daily (AUC0-12h=25.3 [range 2.4-89.7] mcgh/mL; n=18) or to the ganciclovir systemic exposures obtained in adults from 900 mg dose of VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.. 8.5 Geriatric Use. Studies of VALCYTE for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because renal clearance decreases with age, VALCYTE should be administered with consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 8.6Renal Impairment. Dose reduction is recommended when administering VALCYTE to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].For adult patients on hemodialysis (CrCl less than 10 mL/min), VALCYTE tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the CYTOVENE(R)-IV complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 8.7Hepatic Impairment The safety and efficacy of VALCYTE have not been studied in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function. (2.5, 5.2, 8.5, 8.6). Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function. (2.5, 5.2, 8.5, 8.6). 5.1Hematologic Toxicity. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE should be avoided if the absolute neutrophil count is less than 500 cells/uL, the platelet count is less than 25,000/uL, or the hemoglobin is less than g/dL. VALCYTE should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within to days after discontinuing drug. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving VALCYTE [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/uL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to VALCYTE because of increased plasma concentrations of ganciclovir after VALCYTE administration [see Clinical Pharmacology (12.3)].. 5.2Acute Renal Failure. Acute renal failure may occur in:Elderly patients with or without reduced renal function. Caution should be exercised when administering VALCYTE to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)].Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering VALCYTE to patients receiving potential nephrotoxic drugs.Patients without adequate hydration. Adequate hydration should be maintained for all patients.. Elderly patients with or without reduced renal function. Caution should be exercised when administering VALCYTE to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)].. Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering VALCYTE to patients receiving potential nephrotoxic drugs.. Patients without adequate hydration. Adequate hydration should be maintained for all patients.. 5.3Impairment of Fertility. Based on animal data and limited human data, VALCYTE at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of VALCYTE [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. 5.4Fetal Toxicity. Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, VALCYTE has the potential to cause birth defects. Pregnancy should be avoided in female patients taking VALCYTE and in females with male partners taking VALCYTE. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with VALCYTE [see Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. 5.5Mutagenesis and Carcinogenesis. Animal data indicate that ganciclovir is mutagenic and carcinogenic. VALCYTE should therefore be considered potential carcinogen in humans [see Dosage and Administration (2.6), Nonclinical Toxicology (13.1)].