Valganciclovir 450 mg Tablet, Film Coated, 10-count — NDC 31722-832-32 (Billing 31722-0832-32)

12 CLINICAL PHARMACOLOGY

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

12.3Pharmacokinetics Valganciclovir is a 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 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 +

9.7C max (mcg/mL) 58 5.61 +

1.52Absolute oral bioavailability (%) 32 59.4 +

6.1Elimination half-life (hr) 73 4.08 +

0.76Renal 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 Parameter Value (Mean + SD) Heart Transplant Recipients (N=17) Liver Transplant Recipients (N=75) Kidney Transplant Recipients* (N=68) AUC0-24h (mcg ∙ h/mL) 40.2 + 11.8 46.0 + 16.1 48.2 +

14.6Cmax (mcg/mL) 4.9 + 1.1 5.4 + 1.5 5.3 +

1.5Elimination half-life (hr) 6.58 + 1.50 6.18 + 1.42 6.77 +

1.25The 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 Tablets 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 1–2% over 0.5– 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 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 Creatinine Clearance* (mL/min) N Apparent Clearance (mL/min) Mean ± SD AUC last (mcg·h/mL) Mean ± SD Half-life (hours) Mean ± SD 51-70… [Excerpted — this section continues on DailyMed.]

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

12.3Pharmacokinetics Valganciclovir is a 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 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 +

9.7C max (mcg/mL) 58 5.61 +

1.52Absolute oral bioavailability (%) 32 59.4 +

6.1Elimination half-life (hr) 73 4.08 +

0.76Renal 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 Parameter Value (Mean + SD) Heart Transplant Recipients (N=17) Liver Transplant Recipients (N=75) Kidney Transplant Recipients* (N=68) AUC0-24h (mcg ∙ h/mL) 40.2 + 11.8 46.0 + 16.1 48.2 +

14.6Cmax (mcg/mL) 4.9 + 1.1 5.4 + 1.5 5.3 +

1.5Elimination half-life (hr) 6.58 + 1.50 6.18 + 1.42 6.77 +

1.25The 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 Tablets 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 1–2% over 0.5– 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 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 Creatinine Clearance* (mL/min) N Apparent Clearance (mL/min) Mean ± SD AUC last (mcg·h/mL) Mean ± SD Half-life (hours) Mean ± SD 51-70 6 249 ± 99 49.5 ± 22.4 4.85 ± 1.4 21-50 6 136 ± 64 91.9 ± 43.9 10.2 ± 4.4 11-20 6 45 ± 11 223 ± 46 21.8 ± 5.2 ≤10 6 12.8 ± 8 366 ± 66 67.5 ±… [Excerpted — this section continues on DailyMed.]

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 valganciclovir tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with intravenous ganciclovir solution (5 mg per kg twice daily for 21 days, then 5 mg per kg once daily for 7 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 log 10 , and the median CD4 cell count was 23 cells/mm 3 .

A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and Week 4 was the primary outcome measurement of the 3-week induction therapy. Table 19 provides the outcomes at 4 week Table 19 Week 4 Masked Review of Retinal Photographs in CMV Retinitis Study Intravenous Ganciclovir Valganciclovir Tablets Determination of CMV retinitis progression at Week 4 N=80 N=80 Progressor Non-progressor 7 63 7 64 Death Discontinuations due to Adverse Events Failed to return 2 1 1 1 2 1 CMV not confirmed at baseline or no interpretable baseline photos 6 5 Maintenance Therapy of CMV Retinitis: No comparative clinical data are available on the efficacy of valganciclovir tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label valganciclovir tablets after Week 4.

However, the AUC for ganciclovir is similar following administration of 900 mg valganciclovir tablets once daily and 5 mg per kg intravenous ganciclovir once daily. Although the ganciclovir C max is lower following valganciclovir tablets administration compared to intravenous ganciclovir, it is higher than the C max obtained following oral ganciclovir administration. Therefore, use of valganciclovir tablets as maintenance therapy is supported by a 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: A 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 valganciclovir: 1 oral ganciclovir) to receive either valganciclovir tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a 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 6 months post-transplant was similar between the valganciclovir 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 valganciclovir group compared with the ganciclovir group. These results are summarized in Table 20. Mortality at six months was 3.7% (9/244) in the valganciclovir group and 1.6% (2/126) in the oral ganciclovir group.

Table 20 Percentage of Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome by Organ Type: Endpoint Committee, 6 Month ITT Population CMV Disease 1 Tissue-Invasive CMV Disease CMV Syndrome 2 Organ VGCV(N=239) GCV(N=125) VGCV (N=239) GCV (N=125) VGCV (N=239) GCV (N=125) Liver 19 % 12 % 14 % 3 % 5 % 8 % (n=177) (22 / 118) (7 / 59) (16 / 118) (2 / 59) (6 / 118) (5 / 59) Kidney 6 % 23 % 1 % 5 % 5 % 18 % (n=120) (5 / 81) (9 / 39) (1 / 81) (2 / 39) (4 / 81) (7 / 39) Heart 6 % 10 % 0 % 5 % 6 % 5 % (n=56) (2 / 35) (2 / 21) (0 / 35) (1 / 21) (2 / 35) (1 / 21) Kidney / Pancreas 0 % 17 % 0 % 17 % 0% 0 % (n=11) (0 / 5) (1 / 6) (0 / 5) (1 / 6) (0 / 5) (0 / 6) 1 Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome 2 CMV syndrome was defined as evi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have not been conducted with valganciclovir. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a 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 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose, there was a 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, a 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 a 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 5 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.