Valganciclovir Hydrochloride

1 INDICATIONS AND USAGE Valganciclovir for oral solution is a deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for: Pediatric Patients ( 1.2 ) Prevention of CMV disease in kidney and heart transplant patients at high risk. 1.2 Pediatric Patients Prevention of CMV Disease: Valganciclovir 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 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 should be taken with food. ( 2.1 , 12.3 ) 2.1 General Dosing Information Valganciclovir for oral solution 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 )] . 2.3 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/1.73m 2 , then a maximum value of 150 mL/min/1.73m 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* 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 *The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used 1 . 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 10 mg increment for the actual deliverable dose. The oral dispenser is graduated in 0.2 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. modified Schwartz formula 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 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 2°C to 8°C (36°F to 46°F) 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 )] . 2.6 Handling and Disposal Caution should be exercised in the handling of valganciclovir for oral solution. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling, the powder for oral solution, and the constituted oral solution [see Warnings and Precautions ( 5.4, 5.5 )] . Avoid direct contact with 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 contact AvKARE at 1-855-361-3993 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. 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 41 Nausea 30 Vomiting 21 Abdominal pain 15 General disorders and administrative site conditions Pyrexia 31 Nervous system disorders Headache 22 Insomnia 16 Neuropathy peripheral 9 Paresthesia 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 19 500 to < 750 17 750 to < 1000 17 Anemia: Hemoglobin g/dL < 6.5 7 6.5 to < 8.0 13 8.0 to < 9.5 16 Thrombocytopenia: Platelets/µL < 25000 4 25000 to < 50000 6 50000 to < 100000 22 Serum Creatinine: mg/dL > 2.5 3 > 1.5 to 2.5 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 1-4 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 for oral solution 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 1-4 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 Valganciclovir Tablets (N=244) % Ganciclovir Capsules (N=126) % Neutropenia: ANC/µL < 500 5 3 500 to < 750 3 2 750 to < 1000 5 2 Anemia: Hemoglobin g/dL < 6.5 1 2 6.5 to < 8.0 5 7 8.0 to < 9.5 31 25 Thrombocytopenia: Platelets/µL < 25000 0 2 25000 to < 50000 1 3 50000 to < 100000 18 21 Serum Creatinine: mg/dL > 2.5 14 21 > 1.5 to 2.5 45 47 *Laboratory abnormalities are those reported by investigators. Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients* Laboratory Abnormalities Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Neutropenia: ANC/µL < 500 9 10 500 to < 750 6 6 750 to < 1000 7 5 Anemia: Hemoglobin g/dL < 6.5 0 1 6.5 to < 8.0 5 1 8.0 to < 9.5 17 15 Thrombocytopenia: Platelets/µL < 25000 0 0 25000 to < 50000 1 0 50000 to < 100000 7 3 Serum Creatinine: mg/dL > 2.5 17 14 > 1.5 to 2.5 50 48 *Laboratory abnormalities are those reported by investigators. Other adverse drug reactions from valganciclovir in clinical trials in CMV retinitis and solid organ transplant patients Other adverse drug reactions with valganciclovir 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 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 for oral solution 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 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 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of valganciclovir. 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 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 were similar to those identified during the clinical trials. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 PK parameter N Value (Mean ± SD) AUC 0-24h (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) *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. 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 Value (Mean ± SD) Parameter Heart Transplant Recipients (N=17) Liver Transplant Recipients (N=75) Kidney Transplant Recipients* (N=68) AUC 0-24h (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 * Includes kidney-pancreas The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received valganciclovir for 100 days. Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of valganciclovir are provided in Table 12. Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with Valganciclovir 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 mcg/mL 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 mg 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 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. 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 Estimated Apparent Clearance AUC last Half-life Creatinine Clearance* (mL/m i n) (mcg · h/mL) (hours) (mL/min) N Mean ± SD Mean ± SD Mean ± SD 51 to 70 6 249 ± 99 49.5 ± 22.4 4.85 ± 1.4 21 to 50 6 136 ± 64 91.9 ± 43.9 10.2 ± 4.4 11 to 20 6 45 ± 11 223 ± 46 21.8 ± 5.2 ≤10 6 12.8 ± 8 366 ± 66 67.5 ± 34 *Creatinine clearance calculated from 24-hour urine collection. Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following valganciclovir 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 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 Organ PK Parameter mean (SD) Age Group < 4 months 4 months to ≤ 2 years > 2 to < 12 years ≥ 12 years Heart (N=26) N AUC 0-24h (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 0-24h (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 0-24h (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) N= number of patients, NA=not applicable a Ages ranged from 26 to 124 days. Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of valganciclovir 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 [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 0-12 ↑ 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 0-12 ↑ 50 ± 26% (range: 22% to 110%) C max ↑ 36 ± 36% (range: -27% to 94%)