Valganciclovir Hydrochloride Powder,

1 INDICATIONS AND USAGE Valganciclovir hydrochloride is a 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. 1.1 Adult Patients Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)]. Prevention of CMV Disease: Valganciclovir tablets are 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)]. 1.2 Pediatric Patients Prevention of CMV Disease: Valganciclovir for oral solution 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) ].

2 DOSAGE AND ADMINISTRATION Adult Dosage ( 2.2 ) Treatment of CMV retinitis Induction: 900 mg (two 450 mg tablets) twice a day for 21 days Maintenance: 900 mg (two 450 mg tablets) once a day Prevention of CMV disease in heart or kidney-pancreas transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 100 days post-transplantation Prevention of CMV disease in kidney transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 200 days post-transplantation Pediatric Dosage ( 2.3 ) Prevention of CMV disease in kidney transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 200 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children) Prevention of CMV disease in heart transplant patients 1 month to 16 years of age Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children) Valganciclovir for oral solution and tablets should be taken with food. ( 2.1 , 12.3 ) Valganciclovir tablets should not be broken or crushed. ( 2.6 ) Adult patients should use valganciclovir tablets, not valganciclovir for oral solution. ( 2.1 ) Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis a dose recommendation cannot be given. ( 2.5 , 8.6 , 12.3 ) 2.1 General Dosing Information Adult patients should use valganciclovir tablets, not valganciclovir for oral solution. Valganciclovir for oral solution and tablets should be taken with food [see Clinical Pharmacology (12.3)]. Valganciclovir for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4) ]. 2.2 Recommended 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 a 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 a day. Prevention of CMV Disease: For adult patients who have received a heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 100 days post-transplantation. For adult patients who have received a kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 200 days post-transplantation. 2.3 Recommended Dosage in Pediatric Patients Prevention of CMV Disease in Pediatric Kidney Transplant Patients: For pediatric kidney transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7 x BSA x 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 1 month to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of transplantation until 100 days post-transplantation. The recommended once daily dosage of valganciclovir for oral solution is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below: Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73 m 2 , then a maximum value of 150 mL/min/1.73 m 2 should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1. Table 1 k Values According to Pediatric Patient Age * *The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used 1 . k value Pediatric Patient Age 0.33 Infants less than 1 year of age with low birth weight for gestational age 0.45 Infants less than 1 year of age with birth weight appropriate for gestational age 0.45 Children aged 1 to less than 2 years 0.55 Boys aged 2 to less than 13 years Girls aged 2 to less than 16 years 0.7 Boys aged 13 to 16 years Monitor 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. A 50 mg dose is equivalent to 1 mL. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valganciclovir for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, valganciclovir 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 valganciclovir tablets, pediatric patients should be assessed for the ability to swallow tablets. Figure 1 2.4 Preparation of Valganciclovir 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, valganciclovir 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 a graduated cylinder. Shake the valganciclovir for oral solution 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 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. This prepared solution contains 50 mg of valganciclovir free base per 1 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 2ºC to 8ºC (36ºF to 46ºF) 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 2 oral dispensers should be dispensed to the patient [see Patient Counseling Information (17 )] . 2.5 Dosage 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), a dose recommendation for valganciclovir tablets cannot be given [see Use in Specific Populations (8.5 , 8.6 ), Clinical Pharmacology (12.3)]. Table 2 Dosage Recommendations for Adult Patients with Impaired Renal Function *An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas: Valganciclovir 450 mg Tablets CrCl * (mL/min) Induction Dose Maintenance/ Prevention Dose ≥ 60 900 mg twice daily 900 mg once daily 40 to 59 450 mg twice daily 450 mg once daily 25 to 39 450 mg once daily 450 mg every 2 days 10 to 24 450 mg every 2 days 450 mg twice weekly < 10 (on hemodialysis) not recommended not recommended (140 – age [years]) x (body weight [kg]) For males = —————————————————— (72) x (serum creatinine [mg/dL]) For females = 0.85 x male value Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3 )] . 2.6 Handling and Disposal Caution should be exercised in the handling of valganciclovir tablets and valganciclovir for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered a 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 valganciclovir for oral solution according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity). 2

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 valganciclovir 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 valganciclovir for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Valganciclovir, a 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 valganciclovir hydrochloride. Adverse Reactions in Adults: Treatment of CMV Retinitis in AIDS Patients: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions reported by patients receiving valganciclovir tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 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 valganciclovir tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/µL) were 11% for patients receiving valganciclovir tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 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 valganciclovir tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show pooled selected adverse reactions and abnormal laboratory values from these patients. Table 3 Pooled Selected Adverse Reactions Reported in greater than or equal to 5% of Patients who Received Valganciclovir Tablets Maintenance Therapy for CMV Retinitis Patients with CMV Retinitis Adverse Reactions according to Body System Valganciclovir Tablets (N=370) % Gastrointestinal system Diarrhea Nausea Vomiting Abdominal pain 41 30 21 15 General disorders and administrative site conditions Pyrexia 31 Nervous system disorders Headache Insomnia Neuropathy peripheral Paresthesia 22 16 9 8 Eye disorders Retinal detachment 15 Table 4 Pooled Selected Laboratory Abnormalities Reported in Patients Who Received Valganciclovir Tablets Maintenance Therapy for the Treatment of CMV Retinitis Patients with CMV Retinitis Laboratory Abnormalities Valganciclovir Tablets (N=370) % Neutropenia: ANC/µL < 500 500 to < 750 750 to < 1000 19 17 17 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8.0 8.0 to < 9.5 7 13 16 Thrombocytopenia: Platelets/µL < 25000 25000 to < 50000 50000 to < 100000 4 6 22 Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5 3 12 Prevention of CMV Disease in Solid Organ Transplant Patients: Table 5 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received valganciclovir 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 5 Percentage of Selected Grades 1 to 4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients From a Study of Solid Organ Transplant Patients Adverse Reactions Valganciclovir Tablets (N=244) % Oral Ganciclovir (N=126) % Gastrointestinal disorders Diarrhea 30 29 Nausea 23 23 Vomiting 16 14 Nervous system disorders Tremors 28 25 Headache 22 27 Insomnia 20 16 General disorders and administration site conditions Pyrexia 13 14 Table 6 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 valganciclovir did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients. Table 6 Percentage of Selected Grades 1 to 4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients Adverse Reactions Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Gastrointestinal disorders Diarrhea 26 31 Nausea 11 11 Vomiting 3 6 Nervous system disorders Tremors 12 17 Headache 10 6 Insomnia 7 6 General disorders and administration site conditions Pyrexia 12 9 Table 7 and Table 8 show selected laboratory abnormalities reported with valganciclovir tablets in two trials in solid organ transplant patients. Table 7 Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients* *Laboratory abnormalities are those reported by investigators. Laboratory Abnormalities Valganciclovir Tablets (N=244) % Ganciclovir Capsules (N=126) % Neutropenia: ANC/µL < 500 500 to < 750 750 to < 1000 5 3 5 3 2 2 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8.0 8.0 to < 9.5 1 5 31 2 7 25 Thrombocytopenia: Platelets/µL < 25000 25000 to < 50000 50000 to < 100000 0 1 18 2 3 21 Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5 14 45 21 47 Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients* *Laboratory abnormalities are those reported by investigators. Laboratory Abnormalities Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Neutropenia: ANC/µL < 500 500 to < 750 750 to < 1000 9 6 7 10 6 5 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8.0 8.0 to < 9.5 0 5 17 1 1 15 Thrombocytopenia: Platelets/µL < 25000 25000 to < 50000 50000 to < 100000 0 1 7 0 0 3 Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5 17 50 14 48 Other adverse drug reactions from valganciclovir hydrochloride in clinical trials in CMV retinitis and solid organ transplant patients Other adverse drug reactions with valganciclovir hydrochloride 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 pain Gastrointestinal disorders: dyspepsia, constipation, abdominal distention, mouth ulceration General disorders and administration site conditions: fatigue, pain, malaise, asthenia, chills, peripheral edema Hepatobiliary disorders: hepatic function abnormal Infections and infestations: candida infections including oral candidiasis, upper respiratory tract infection, influenza, urinary tract infection, pharyngitis/nasopharyngitis, postoperative wound infection Injury, poisoning, and procedural complications: postoperative complications, wound secretion Metabolic and nutrition disorders: decreased appetite, hyperkalemia, hypophosphatemia, weight decreased Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms Nervous system disorders: insomnia, neuropathy peripheral, dizziness Psychiatric disorders: depression, anxiety Renal and urinary disorders: renal impairment, creatinine clearance renal decreased, blood creatinine increased, hematuria Respiratory, thoracic and mediastinal disorders: cough, dyspnea Skin and subcutaneous tissues disorders: dermatitis, night sweats, pruritus Vascular disorders : hypotension Other adverse reactions with valganciclovir hydrochloride 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: arrhythmia Ear and labyrinth disorders: deafness Eye disorders: macular edema Gastrointestinal disorders: pancreatitis Hemorrhage: potentially life-threatening bleeding associated with thrombocytopenia Immune system disorders: hypersensitivity Infections and infestations: cellulitis, sepsis Injury, poisoning, and procedural complications: postoperative pain, wound dehiscence Investigations: aspartate aminotransferase increased, alanine aminotransferase increased Musculoskeletal and connective tissue disorders: limb pain Nervous system disorders: seizure, dysguesia (taste disturbance) Psychiatric disorders: confusional state, agitation, psychotic disorder, hallucinations Renal and urinary disorders: renal failure Adverse Reactions in Pediatric Patients: Valganciclovir for oral solution and tablets have been studied in 179 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 3 weeks to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 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 valganciclovir hydrochloride 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 a 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 valganciclovir hydrochloride 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/μL) was higher in pediatric kidney transplant patients treated with valganciclovir hydrochloride 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 valganciclovir hydrochloride. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of valganciclovir hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As valganciclovir hydrochloride is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir. - Anaphylactic reaction - Agranulocytosis - Granulocytopenia In general, the adverse reactions reported during the postmarketing use of valganciclovir hydrochloride were similar to those identified during the clinical trials.

12.3 Pharmacokinetics Valganciclovir is a prodrug of ganciclovir. Valganciclovir C max 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 10 Ganciclovir Pharmacokinetics* in Healthy Volunteers and HIV-positive/CMV-positive Adults Administered Valganciclovir Tablets 900 mg Once Daily with Food *Data 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. PK parameter N Value (Mean ± SD) AUC 0 to 24h (mcg ∙ h/mL) 57 29.1 ± 9.7 C max (mcg/mL) 58 5.61 ± 1.52 Absolute oral bioavailability (%) 32 59.4 ± 6.1 Elimination half-life (hr) 73 4.08 ± 0.76 Renal clearance (mL/min/kg) 20 3.21 ± 0.75 (1 study, n=20) The systemic ganciclovir exposures attained following administration of 900 mg valganciclovir tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11). Table 11 Ganciclovir Pharmacokinetics in Solid Organ Transplant Recipients Administered Valganciclovir Tablets 900 mg Once Daily with Food *Includes kidney-pancreas Parameter Value (Mean ± SD) Heart Transplant Recipients (N=17) Liver Transplant Recipients (N=75) Kidney Transplant Recipients* (N=68) AUC 0 to 24h (mcg ∙ h/mL) 40.2 ± 11.8 46.0 ± 16.1 48.2 ± 14.6 C max (mcg/mL) 4.9 ± 1.1 5.4 ± 1.5 5.3 ± 1.5 Elimination half-life (hr) 6.58 ± 1.50 6.18 ± 1.42 6.77 ± 1.25 The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir hydrochloride administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received valganciclovir hydrochloride for 100 days. Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of valganciclovir hydrochloride are provided in Table 12. Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with Valganciclovir Tablets a Steady state ganciclovir PK was assessed after administration of valganciclovir tablets (875 mg once daily) with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) to 16 HIV-positive subjects. Valganciclovir Ganciclovir Absorption T max (h) median (min-max) (fed conditions) 2.18 1.7h to 3.0h Food effect (high fat meal/fasting): PK parameter ratio and 90% confidence interval a C max : 1.14 (0.95, 1.36) AUC: 1.30 (1.07, 1.51) a T max : ↔ Distribution % Bound to human plasma proteins ( ex vivo ) Unknown 1 to 2% over 0.5 to 51 mcg/mL Cerebrospinal fluid penetration Unknown Yes Metabolism Hydrolyzed by intestinal and liver esterases No significant metabolism Elimination Dose proportionality AUC was dose proportional under fed conditions across a valganciclovir dose range of 450 to 2625 mg Major route of elimination Metabolism to ganciclovir Glomerular filtration and active tubular secretion t 1/2 (h) See Tables 10 and 11 % Of dose excreted in urine Unknown % Of dose excreted in feces Unknown Specific Populations: Renal Impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir 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 13 Pharmacokinetics of Ganciclovir from a Single Oral Dose of 900 mg Valganciclovir Tablets *Creatinine clearance calculated from 24-hour urine collection. Estimated Creatinine Clearance* (mL/min) N Apparent Clearance (mL/min) Mean ± SD AUC last (mcg∙h/mL) Mean ± SD Half-life (hours) Mean ± SD 51 to 70 21 to 50 11 to 20 ≤ 10 6 6 6 6 249 ± 99 136 ± 64 45 ± 11 12.8 ± 8 49.5 ± 22.4 91.9 ± 43.9 223 ± 46 366 ± 66 4.85 ± 1.4 10.2 ± 4.4 21.8 ± 5.2 67.5 ± 34 Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following valganciclovir hydrochloride administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use valganciclovir tablets because the daily dose of valganciclovir 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 4 months to 16 years, and in 16 pediatric heart transplant patients less than 4 months of age. In these studies, patients received oral doses of valganciclovir (either valganciclovir 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 14 Ganciclovir Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patients Administered Valganciclovir Hydrochloride N=number of patients, NA=not applicable a Ages ranged from 26 to 124 days. Organ PK Parameter mean (SD) < 4 months Age Group 4 months to ≤ 2 years > 2 to < 12 years ≥ 12 years Heart (N=26) N AUC 0 to 24h (mcg ∙ h/mL) C max (mcg/mL) t 1/2 (h) 14 a 66.3 (20.5) 10.8 (3.30) 3.5 (0.87) 6 55.4 (22.8) 8.2 (2.5) 3.8 (1.7) 2 59.6 (21.0) 12.5 (1.2) 2.8 (0.9) 4 60.6 (25.0) 9.5 (3.3) 4.9 (0.8) Kidney (N=31) N AUC 0 to 24h (mcg ∙ h/mL) C max (mcg/mL) t 1/2 (h) NA 2 67.6 (13.0) 10.4 (0.4) 4.5 (1.5) 10 55.9 (12.1) 8.7 (2.1) 4.8 (1.0) 19 47.8 (12.4) 7.7 (2.1) 6.0 (1.3) Liver (N=17) N AUC 0 to 24h (mcg ∙ h/mL) C max (mcg/mL) t 1/2 (h) NA 9 69.9 (37.0) 11.9 (3.7) 2.8 (1.5) 6 59.4 (8.1) 9.5 (2.3) 3.8 (0.7) 2 35.4 (2.8) 5.5 (1.1) 4.4 (0.2) Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of valganciclovir hydrochloride 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 valganciclovir hydrochloride [see Drug Interactions (7)]. Table 15 and Table 16 provide a 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 15 Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK) Parameter Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function) Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 No effect on ganciclovir PK parameters observed Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 5 mg/kg IV twice daily 11 No effect on ganciclovir PK parameters observed 5 mg/kg IV once daily 11 No effect on ganciclovir PK parameters observed Probenecid 500 mg every 6 hours 1000 mg every 8 hours 10 AUC ↑ 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance ↓ 22 ± 20% (range: -54% to -4%) Table 16 Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered Drug Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK) Parameter Oral cyclosporine at therapeutic doses 5 mg/kg infused over 1 hour every 12 hours 93 In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations. Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No PK interaction observed (patients with normal renal function) Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 No effect on trimethoprim PK parameters observed Didanosine 200 mg every 12 hours 5 mg/kg IV twice daily 11 AUC 0 to 12 ↑­70 ± 40% (range: 3% to 121%) C max ­↑49 ± 48% (range: -28% to 125%) Didanosine 200 mg every 12 hours 5 mg/kg IV once daily 11 AUC 0 to 12 ↑­50 ± 26% (range: 22% to 110%) C max ­ ↑36 ± 36% (range: -27% to 94%)