1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir Tablets, USP 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, USP 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 Tablets, USP are indicated for the prevention of CMV disease in heart transplant patients (4 months to 16 years of age) at high risk [see Clinical Studies (14.2)] .

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.1 General Dosing Information

• Adult patients should use valganciclovir tablets, not valganciclovir for oral solution.
• Valganciclovir tablets should be taken with food [see Clinical Pharmacology (12.3)] .

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 Heart Transplant Patients: For pediatric heart transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7x BSA x CrCL) should start within 10 days of transplantation until 100 days post-transplantation.

The recommended once daily dosage of valganciclovir tablets 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.

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. 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.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.5 Dosage Recommendation for Adult Patients with Renal Impairment

Serum creatinine levels or 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)] .

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. 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 [see Warnings and Precautions (5.3, 5.4)] . Avoid direct contact with broken or crushed tablets 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 tablets according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity) 2 .

5.1 Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valganciclovir or ganciclovir. Valganciclovir should be avoided if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25,000/µL, or the hemoglobin is less than 8 g/dL. Valganciclovir should also be used with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving valganciclovir [see Adverse Reactions (6.1)] , complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to valganciclovir, because of increased plasma concentrations of ganciclovir after valganciclovir administration [see Clinical Pharmacology (12.3)] .

5.2 Impairment of Fertility

Based on animal data with ganciclovir, valganciclovir 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 valganciclovir [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)] .

5.3 Fetal 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 2-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, valganciclovir has the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir and in females with male partners taking valganciclovir. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir. Similarly, males should be advised to practice barrier contraception during and for at least 90 days following treatment with valganciclovir [see Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.4 Mutagenesis and Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Valganciclovir should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6), Nonclinical Toxicology (13.1)] .

5.5 Acute Renal Failure

Acute renal failure may occur in:

• Elderly patients with or without reduced renal function. Caution should be exercised when administering valganciclovir 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 valganciclovir to patients receiving potential nephrotoxic drugs.
• Patients without adequate hydration. Adequate hydration should be maintained for all patients.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event 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 events known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir.

Adverse Events 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 events 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%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received valganciclovir tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive 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 events and abnormal laboratory values data 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 the pooled adverse event data and abnormal laboratory values from these patients.

Prevention of CMV Disease in Selected Solid Organ Transplantation: Table 5 shows selected adverse events regardless of severity and drug relationship 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 events were of mild or moderate intensity.

Table 6 shows selected adverse events regardless of severity and drug relationship 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 starting within 10 days post-transplant 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.

Adverse events not included in Table 5 and Table 6, which either occurred at a frequency of greater than or equal to 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients with a frequency of less than 5% are listed below.

Allergic reactions: valganciclovir hypersensitivity

Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia

Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion

Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites

General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness

Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia, febrile neutropenia

Hepatobiliary disorders: abnormal hepatic function

Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection

Injury, poisoning, and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence

Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia

Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain

Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation

Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion

Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne

Vascular disorders: hypotension

Laboratory abnormalities reported with valganciclovir tablets in two studies in solid adult organ transplant patients are listed in Table 7 and Table 8.

Adverse Events in Pediatric Patients:

Valganciclovir for oral solution and tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months 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 100 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 events (greater than 10% of patients), regardless of seriousness and drug relationship in pediatric solid organ transplant patients taking valganciclovir until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, hypertension, vomiting, anemia, neutropenia, constipation, nausea and transplant rejection.

In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse events 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 with 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.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following adverse events 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 events associated with ganciclovir might also occur with valganciclovir.

–  Anaphylaxis

–  Decreased fertility in males

In general, the adverse events reported during the postmarketing use of valganciclovir were similar to those identified during the clinical trials.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy

Risk Summary

After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, valganciclovir 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 valganciclovir 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 risk

Most maternal CMV infections are asymptomatic or they may be associated with a 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 a 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 Data

At doses resulting in two-times the human exposure of ganciclovir (all dose comparisons presented are based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryofetal 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 embryofetal 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 embryofetal 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 a concentration range of 1 to 10 mg/mL.

8.2 Lactation

Risk Summary

No 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. 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 valganciclovir 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, 5.2, 5.3, 5.4), Nonclinical Toxicology (13.1)] .

8.3 Females and Males of Reproductive Potential

Pregnancy Testing                                                                        

Females of reproductive potential should undergo pregnancy testing before initiation of valganciclovir [see Use in Specific Populations (8.1)] .

Contraception

Females

Because of the mutagenic and teratogenic potential of valganciclovir, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir [see Dosage and Administration (2.6), Warnings and Precautions (5.3, 5.4), Nonclinical Toxicology (13.1)] .

Males

Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following, treatment with valganciclovir [see Dosage and Administration (2.6), Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)] .

Infertility

Valganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)] .

8.4 Pediatric Use

Valganciclovir tablets are indicated for the prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)].

Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). Valganciclovir was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation.

The use of valganciclovir for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age is based on two studies (Study 1 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 3 was a pharmacokinetic and safety study of valganciclovir in pediatric heart transplant patients less than 4 months of age who received a single dose of valganciclovir oral solution on each of two consecutive days. A 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 1 month of age. However, due to uncertainty in model predictions for neonates, valganciclovir is not indicated for prophylaxis in this age group.

The safety and efficacy of valganciclovir tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of valganciclovir for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or valganciclovir 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 7 days to 3 months of age, a dose of 16 mg per kg twice daily of valganciclovir for oral solution provided ganciclovir systemic exposures (median AUC 0-12h = 23.6 [range 16.8 – 35.5] mcg ∙h/mL; n = 6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC 0-12h = 25.3 [range 2.4 – 89.7] mcg ∙h/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of valganciclovir tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of valganciclovir 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.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Studies of valganciclovir for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of valganciclovir 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. Valganciclovir 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 elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .

8.6 Renal Impairment

Dose reduction is recommended when administering valganciclovir to patients with renal impairment
[see  Dosage and Administration (2.5),  Warnings and Precautions (5.5), Clinical Pharmacology (12.3)] .

For adult patients on hemodialysis (CrCl less than 10 mL/min) valganciclovir tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the Cytovene ®-IV complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see  Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The safety and efficacy of valganciclovir have not been studied in patients with hepatic impairment.

12.1 Mechanism of Action

Valganciclovir is an antiviral drug  [see  Microbiology (12.4)] .

12.3 Pharmacokinetics

Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for valganciclovir tablets [see  Dosage and Administration (2.5)] .

Pharmacokinetics in Adults: The pharmacokinetics of valganciclovir and 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.

The ganciclovir pharmacokinetic parameters following administration of 900 mg valganciclovir tablets and 5 mg per kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 10.

Table 10 Mean Ganciclovir Pharmacokinetic * Measures in Healthy Volunteers and HIV-positive/CMV-positive Adults at Maintenance Dosage

Formulation	Valganciclovir Tablets	Intravenous Ganciclovir	Ganciclovir Capsules
* 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.
Dosage	900 mg once daily with food	5 mg/kg once daily	1000 mg three times daily with food
AUC 0-24h (µg∙h/mL)	29.1 ± 9.7 (3 studies, n=57)	26.5 ± 5.9 (4 studies, n=68)	Range of means 12.3 to 19.2 (6 studies, n=94)
C max (µg/mL)	5.61 ± 1.52 (3 studies, n=58)	9.46 ± 2.02 (4 studies, n=68)	Range of means 0.955 to 1.40 (6 studies, n=94)
Absolute oral bioavailability (%)	59.4 ± 6.1 (2 studies, n=32)	Not Applicable	Range of means 6.22 ± 1.29 to 8.53 ± 1.53 (2 studies, n=32)
Elimination half-life (hr)	4.08 ± 0.76 (4 studies, n=73)	3.81 ± 0.71 (4 studies, n=69)	Range of means 3.86 to 5.03 (4 studies, n=61)
Renal clearance (mL/min/kg)	3.21 ± 0.75 (1 study, n=20)	2.99 ± 0.67 (1 study, n=16)	Range of means 2.67 to 3.98 (3 studies, n=30)

The area under the plasma concentration-time curve (AUC) of ganciclovir administered as valganciclovir tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg per kg once daily). The C max of ganciclovir following valganciclovir administration is 40% lower than the C max following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC 0-24h and C max following oral ganciclovir administration (1000 mg three times daily) are lower relative to valganciclovir and intravenous ganciclovir. The ganciclovir C min following intravenous ganciclovir and valganciclovir administration are less than the ganciclovir C min following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of valganciclovir tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.

Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*

*Plasma concentration-time profiles for ganciclovir (GCV) from valganciclovir (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (n=21 and n=18, respectively) in HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7x higher following administration of 900 mg valganciclovir tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetic evaluation (see Table 11).

Table 11 Mean Ganciclovir Pharmacokinetic Measures by Organ Transplant Type

Parameter	Ganciclovir Capsules	Valganciclovir Tablets
* Includes kidney-pancreas
Dosage	1000 mg three times daily with food Mean ± SD	900 mg once daily with food Mean ± SD
Heart Transplant Recipients	N=13	N=17
AUC 0-24h (µg ∙h/mL)	26.6 ± 11.6	40.2 ± 11.8
C max (µg/mL)	1.4 ± 0.5	4.9 ± 1.1
Elimination half-life (hr)	8.47 ± 2.84	6.58 ± 1.50
Liver Transplant Recipients	N=33	N=75
AUC 0-24h (µg ∙h/mL)	24.9 ± 10.2	46.0 ± 16.1
C max (µg/mL)	1.3 ± 0.4	5.4 ± 1.5
Elimination half-life (hr)	7.68 ± 2.74	6.18 ± 1.42
Kidney Transplant Recipients *	N=36	N=68
AUC 0-24h (µg ∙h/mL)	31.3 ± 10.3	48.2 ± 14.6
C max (µg/mL)	1.5 ± 0.5	5.3 ± 1.5
Elimination half-life (hr)	9.44 ± 4.37	6.77 ± 1.25

The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received valganciclovir for 100 days.

In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC 0-24h achieved with 900 mg valganciclovir was 41.7 ± 9.9 mcg ∙h/mL (n=28) and the AUC 0-24h achieved with the approved dosage of 5 mg per kg intravenous ganciclovir was 48.2 ± 17.3 mcg ∙h/mL (n=27).

Absorption: Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median T max following administration of 450 mg to 2625 mg valganciclovir tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC 24 and C max values are approximately 1% and 3% of those of ganciclovir, respectively.

Food Effects: When valganciclovir tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the C max increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (T max). Valganciclovir should be administered with food [see Dosage and Administration (2.1)] .

Distribution: Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mcg/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703 ± 0.134 L/kg (n=69).

After administration of valganciclovir tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of valganciclovir tablets according to weight is not required.

Metabolism: Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.

Elimination: The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07 ± 0.64 mL/min/kg (n=68) while renal clearance was 2.99 ± 0.67 mL/min/kg (n=16).

The terminal half-life (t ½) of ganciclovir following oral administration of valganciclovir tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 ± 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 ± 0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of valganciclovir was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.

12.4 Microbiology

Mechanism of Action: Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a 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, synthesis 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% (EC 50), vary greatly depending upon a number of factors including the assay used. Thus, the reported EC 50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 µM (0.02 to 5.75 mcg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was 0 to 1 µM (35%), 1.1 to 2 µM (20%), 2.1 to 3 µM (27%), 3.1 to 4 µM (13%), 4.1 to 5 µM (5%), less than 5 µM (less than 1%). Ganciclovir inhibits mammalian cell proliferation (CC 50) in cell culture at higher concentrations ranging from 40 to greater than 1,000 µM (10.21 to greater than 250 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC 50 value= 2.7 to 12 µM (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, 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 16.

The presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in a 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 V. 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 17.

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.

13.1 Carcinogenesis, 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 (5.2)] . 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.

14.1 Adult 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 18 provides the outcomes at 4 weeks.

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 [see Figure 1 in Clinical Pharmacology (12.3)] . 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 19.

Mortality at six months was 3.7% (9/244) in the valganciclovir group and 1.6% (2/126) in the oral ganciclovir group.

Prevention of CMV Disease in Kidney Transplantation: A 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 valganciclovir CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive valganciclovir 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 valganciclovir 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 20.

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.

14.2 Pediatric Patients

Prevention of CMV in Pediatric Heart, Kidney, or Liver Transplantation: Sixty-three children, 4 months to 16 years of age, who had a 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 valganciclovir (valganciclovir for oral solution or tablets). Patients received valganciclovir once daily within 10 days after transplant until a maximum of 100 days post-transplant. The daily doses of valganciclovir were calculated at each study visit based on body surface area and a 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 valganciclovir 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.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature].