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WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS
See full prescribing information for complete boxed warning.
VALCYTE is a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor indicated for:
Adult Patients (1.1)
Pediatric Patients (1.2)
|Adult Dosage (2.2)|
|Treatment of CMV retinitis||Induction: 900 mg (two 450 mg tablets) twice a day for 21 days
Maintenance: 900 mg (two 450 mg tablets) once a day
|Prevention of CMV disease in heart or kidney-pancreas transplant patients||900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 100 days post-transplantation|
|Prevention of CMV disease in kidney transplant patients||900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 200 days post-transplantation|
|Pediatric Dosage (2.3)|
|Prevention of CMV disease in kidney transplant patients 4 months to 16 years of age||Dose once a day within 10 days of transplantation until 200 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children)|
|Prevention of CMV disease in heart transplant patients 1 month to 16 years of age||Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children)|
Hypersensitivity to valganciclovir or ganciclovir (4)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Treatment of Cytomegalovirus (CMV) Retinitis: VALCYTE is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].
Prevention of CMV Disease: VALCYTE is indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].
Prevention of CMV Disease: VALCYTE is indicated for the prevention of CMV disease in kidney transplant patients (4 months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high risk [see Clinical Studies (14.2)].
For dosage recommendations in adult patients with renal impairment [see Dosage and Administration (2.5)].
Treatment of CMV Retinitis:
Prevention of CMV Disease:
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× BSA × CrCL) should start within 10 days of post-transplantation until 200 days post-transplantation.
Prevention of CMV Disease in Pediatric Heart Transplant Patients: For pediatric heart transplant patients 1 month to 16 years of age, the recommended once daily mg dose (7× BSA × CrCL) should start within 10 days of transplantation until 100 days post-transplantation.
The recommended once daily dosage of VALCYTE is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:
Pediatric Dose (mg) = 7 × BSA × CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2, then a maximum value of 150 mL/min/1.73m2 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.
|k value||Pediatric Patient Age|
|0.33||Infants less than 1 year of age with low birth weight for gestational age|
|0.45||Infants less than 1 year of age with birth weight appropriate for gestational age|
|0.45||Children aged 1 to less than 2 years|
|0.55||Boys aged 2 to less than 13 years
Girls aged 2 to less than 16 years
|0.7||Boys aged 13 to 16 years|
Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.
All calculated doses should be rounded to the nearest 10 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. VALCYTE for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, VALCYTE tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. Before prescribing VALCYTE tablets, pediatric patients should be assessed for the ability to swallow tablets.
Prior to dispensing to the patient, VALCYTE for oral solution must be prepared by the pharmacist as follows [see How Supplied/Storage and Handling (16)]:
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)].
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 VALCYTE cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].
|VALCYTE 450 mg Tablets|
|CrCl* (mL/min)||Induction Dose||Maintenance/Prevention Dose|
|≥ 60||900 mg twice daily||900 mg once daily|
|40 – 59||450 mg twice daily||450 mg once daily|
|25 – 39||450 mg once daily||450 mg every 2 days|
|10 – 24||450 mg every 2 days||450 mg twice weekly|
|not recommended||not recommended|
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)].
Caution should be exercised in the handling of VALCYTE tablets and VALCYTE for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, the powder for oral solution, and the constituted oral solution [see Warnings and Precautions (5.3, 5.4)]. Avoid direct contact with broken or crushed tablets, the powder for oral solution, and the constituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.
Handle and dispose VALCYTE according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity)2.
VALCYTE is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)].
Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE should be avoided if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25,000/µL, or the hemoglobin is less than 8 g/dL. VALCYTE 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 VALCYTE [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 VALCYTE, because of increased plasma concentrations of ganciclovir after VALCYTE administration [see Clinical Pharmacology (12.3)].
Based on animal data with ganciclovir, VALCYTE at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of VALCYTE [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
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, VALCYTE has the potential to cause birth defects. Pregnancy should be avoided in female patients taking VALCYTE and in females with male partners taking VALCYTE. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE. Similarly, males should be advised to practice barrier contraception during and for at least 90 days following treatment with VALCYTE [see Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
Animal data indicate that ganciclovir is mutagenic and carcinogenic. VALCYTE should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6), Nonclinical Toxicology (13.1)].
Acute renal failure may occur in:
The following serious adverse events are discussed in greater detail in other sections of the labeling:
The most common adverse events and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with VALCYTE tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with VALCYTE for oral solution or tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.
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 VALCYTE.
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 VALCYTE 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 VALCYTE 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 VALCYTE 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 VALCYTE tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received VALCYTE tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show the pooled adverse event data and abnormal laboratory values from these patients.
|Patients with CMV Retinitis|
|Adverse Events According to Body System||VALCYTE Tablets
|Body as a whole|
|Central and peripheral nervous system|
|Patients with CMV Retinitis|
|Laboratory Abnormalities||VALCYTE Tablets
|500 – < 750||17|
|750 – < 1000||17|
|Anemia: Hemoglobin g/dL|
|6.5 – < 8.0||13|
|8.0 – < 9.5||16|
|25000 – < 50000||6|
|50000 – < 100000||22|
|Serum Creatinine: mg/dL|
|> 1.5 – 2.5||12|
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 VALCYTE 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.
|Adverse Event||VALCYTE Tablets
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 VALCYTE did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients.
|Adverse Event||VALCYTE Tablets Day 100 Post-transplant
|VALCYTE Tablets Day 200 Post-transplant
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||VALCYTE Tablets
|500 – < 750||3||2|
|750 – < 1000||5||2|
|Anemia: Hemoglobin g/dL|
|6.5 – < 8.0||5||7|
|8.0 – < 9.5||31||25|
|25000 – < 50000||1||3|
|50000 – < 100000||18||21|
|Serum Creatinine: mg/dL|
|> 1.5 – 2.5||45||47|
|Laboratory Abnormalities||VALCYTE Tablets Day 100 Post-transplant
|VALCYTE Tablets Day 200 Post-transplant
|500 – < 750||6||6|
|750 – < 1000||7||5|
|Anemia: Hemoglobin g/dL|
|6.5 – < 8.0||5||1|
|8.0 – < 9.5||17||15|
|25000 – < 50000||1||0|
|50000 – < 100000||7||3|
|Serum Creatinine: mg/dL|
|> 1.5 – 2.5||50||48|
Adverse Events in Pediatric Patients:
VALCYTE for oral solution and tablets have been studied in 179 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 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 events (greater than 10% of patients), regardless of seriousness and drug relationship in pediatric solid organ transplant patients taking VALCYTE until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, hypertension, vomiting, anemia, neutropenia, constipation, nausea and transplant rejection. The most frequently reported adverse events (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, dysuria, tremor, pyrexia, hypertension, anemia, blood creatinine increase, vomiting, E. coli urinary tract infection 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 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.
The overall safety profile of VALCYTE was similar with the extension of prophylaxis until Day 200 post-transplant in high risk pediatric kidney transplant patients. However, the incidence of severe neutropenia (ANC<500/µL) was higher in pediatric kidney transplant patients treated with VALCYTE until Day 200 (17/57, 30%) compared to pediatric kidney transplant patients treated until Day 100 (3/63, 5%). There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated 100 or 200 days with VALCYTE.
The following adverse events have been identified during post-approval use of VALCYTE. 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 VALCYTE is rapidly and extensively converted to ganciclovir, any adverse events associated with ganciclovir might also occur with valganciclovir.
In general, the adverse events reported during the postmarketing use of VALCYTE were similar to those identified during the clinical trials.
In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for VALCYTE. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.
|Name of the Concomitant Drug||Change in the Concentration of Ganciclovir or Concomitant Drug||Clinical Comment|
|Zidovudine and VALCYTE each have the potential to cause neutropenia and anemia|
|Probenecid||↑ Ganciclovir||Patients taking probenecid and VALCYTE should be monitored for evidence of ganciclovir toxicity|
|Mycophenolate Mofetil (MMF)||↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
|Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase|
|Patients should be closely monitored for didanosine toxicity|
After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, VALCYTE is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of VALCYTE or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)].
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.
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.
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 VALCYTE because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV [see Boxed Warning, Warnings and Precautions (5.1, 5.2, 5.3, 5.4), Nonclinical Toxicology (13.1)].
Females of reproductive potential should undergo pregnancy testing before initiation of VALCYTE [see Use in Specific Populations (8.1)].
Because of the mutagenic and teratogenic potential of VALCYTE, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE [see Dosage and Administration (2.6), Warnings and Precautions (5.3, 5.4), Nonclinical Toxicology (13.1)].
VALCYTE for oral solution and tablets are indicated for the prevention of CMV disease in pediatric patients 4 months to 16 years of age and in pediatric heart transplant patients 1 month to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)].
The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients 4 months to 16 years of age. Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). VALCYTE was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation. Study 2 was a safety and tolerability study where VALCYTE was administered once daily within 10 days of transplantation for a maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 1 month 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 VALCYTE in pediatric heart transplant patients less than 4 months of age who received a single dose of VALCYTE 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, VALCYTE is not indicated for prophylaxis in this age group.
The safety and efficacy of VALCYTE for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 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 VALCYTE 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 VALCYTE for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of VALCYTE for oral solution provided ganciclovir systemic exposures (median AUC0-12h = 23.6 [range 16.8 – 35.5] 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 (AUC0-12h = 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 VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.
Studies of VALCYTE for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because 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)].
For adult patients on hemodialysis (CrCl less than 10 mL/min) VALCYTE tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the Cytovene®-IV complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
Experience with VALCYTE Tablets: One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's estimated degree of renal impairment.
Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of VALCYTE [see Clinical Pharmacology (12.3)]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Clinical Pharmacology (12.3)].
Experience with Intravenous Ganciclovir: Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:
Hematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia
Hepatotoxicity: hepatitis, liver function disorder
Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine
Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting
Neurotoxicity: generalized tremor, convulsion
VALCYTE contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.
VALCYTE is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. The film-coat applied to the tablets contains Opadry Pink®.
VALCYTE is also available as a powder for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of VALCYTE for oral solution are sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring.
Valganciclovir HCl is a white to off-white crystalline powder with a molecular formula of C14H22N6O5∙HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir HCl is 7.6.
The chemical structure of valganciclovir HCl is:
All doses in this insert are specified in terms of valganciclovir.
Valganciclovir is an antiviral drug [see Microbiology (12.4)].
Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for VALCYTE tablets and VALCYTE for oral solution [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 VALCYTE 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.
|Formulation||VALCYTE Tablets||Intravenous Ganciclovir||Ganciclovir Capsules|
|Dosage||900 mg once daily with food||5 mg/kg once daily||1000 mg three times daily with food|
|AUC0-24h (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)
|Cmax (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 VALCYTE tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg per kg once daily). The Cmax of ganciclovir following VALCYTE administration is 40% lower than the Cmax following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24h and Cmax following oral ganciclovir administration (1000 mg three times daily) are lower relative to VALCYTE and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and VALCYTE administration are less than the ganciclovir Cmin following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of VALCYTE tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.
|Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*|
In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7× higher following administration of 900 mg VALCYTE 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).
|Parameter||Ganciclovir Capsules||VALCYTE Tablets|
|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|
|AUC0-24h (µg∙h/mL)||26.6 ± 11.6||40.2 ± 11.8|
|Cmax (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|
|AUC0-24h (µg∙h/mL)||24.9 ± 10.2||46.0 ± 16.1|
|Cmax (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|
|AUC0-24h (µg∙h/mL)||31.3 ± 10.3||48.2 ± 14.6|
|Cmax (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 VALCYTE administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received VALCYTE for 100 days.
In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC0-24h achieved with 900 mg valganciclovir was 41.7 ± 9.9 mcg∙h/mL (n=28) and the AUC0-24h 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 VALCYTE tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median Tmax following administration of 450 mg to 2625 mg VALCYTE tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of VALCYTE tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC24 and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.
Food Effects: When VALCYTE 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 Cmax increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). VALCYTE 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 VALCYTE tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of VALCYTE 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 (t½) of ganciclovir following oral administration of VALCYTE 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 VALCYTE was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.
Renal Impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg VALCYTE tablets were evaluated in 24 otherwise healthy individuals with renal impairment.
|Estimated Creatinine Clearance
Mean ± SD
Mean ± SD
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 ± 34|
Decreased renal function results in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for patients with impaired renal function.
Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following VALCYTE administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use VALCYTE tablets because the daily dose of VALCYTE tablets required for these patients is less than 450 mg [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].
Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged 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 VALCYTE for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)].
The pharmacokinetics of ganciclovir were similar across organ types and age ranges. Based on a population pharmacokinetic evaluation, clearance is influenced by both body weight and renal function, while the central and peripheral volumes of distribution were influenced by weight [see Dosage and Administration (2.5)]. The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean ganciclovir Cmax, AUC and half-life by age and organ type in studies using the pediatric valganciclovir dosing algorithm are listed in Table 13. 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.
|Organ||PK Parameter mean (SD)||Age Group|
|< 4 months||4 months to ≤ 2 years||> 2 to < 12 years||≥ 12 years|
|N= number of patients|
|Heart||AUC0-24h (µg∙h/mL)||66.3 (20.5)‡||55.4 (22.8)||59.6 (21.0)||60.6 (25.0)|
|(N=26)||Cmax (µg/mL)||10.8 (3.30)||8.2 (2.5)||12.5 (1.2)||9.5 (3.3)|
|t1/2 (h)||3.5 (0.87)||3.8 (1.7)||2.8 (0.9)||4.9 (0.8)|
|Kidney||AUC0-24h (µg∙h/mL)||67.6 (13.0)||55.9 (12.1)||47.8 (12.4)|
|(N=31)||Cmax (µg/mL)||10.4 (0.4)||8.7 (2.1)||7.7 (2.1)|
|t1/2 (h)||4.5 (1.5)||4.8 (1.0)||6.0 (1.3)|
|Liver||AUC0-24h (µg∙h/mL)||69.9 (37.0)||59.4 (8.1)||35.4 (2.8)|
|(N=17)||Cmax (µg/mL)||11.9 (3.7)||9.5 (2.3)||5.5 (1.1)|
|t1/2 (h)||2.8 (1.5)||3.8 (0.7)||4.4 (0.2)|
Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of VALCYTE in elderly patients have not been established. Because elderly individuals frequently have a reduced glomerular filtration rate, renal function should be assessed before and during administration of VALCYTE [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].
Drug Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for VALCYTE [see Drug Interactions (7)].
Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of VALCYTE and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.
Table 14 and Table 15 provide a listing of established drug interaction studies with ganciclovir. Table 14 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 15 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.
|Coadministered Drug||Ganciclovir Dosage||N||Ganciclovir Pharmacokinetic (PK) Parameter|
|Zidovudine 100 mg every 4 hours||1000 mg every 8 hours||12||AUC ↓ 17 ± 25%
(range: -52% to 23%)
|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%)
|Mycophenolate Mofetil (MMF) 1.5 g single dose||IV ganciclovir 5 mg/kg single dose||12||No effect on ganciclovir PK parameters observed (patients with normal renal function)|
|Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir||1000 mg every 8 hours||12||AUC ↓ 21 ± 17%
(range: -44% to 5%)
|Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir||1000 mg every 8 hours||12||No effect on ganciclovir PK parameters observed|
|IV ganciclovir 5 mg/kg twice daily||11||No effect on ganciclovir PK parameters observed|
|IV ganciclovir 5 mg/kg once daily||11||No effect on ganciclovir PK parameters observed|
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||Ganciclovir renal clearance ↓ 16.3%
|Coadministered Drug||Ganciclovir Dosage||N||Coadministered Drug Pharmacokinetic (PK) Parameter|
|Zidovudine 100 mg every 4 hours||1000 mg every 8 hours||12||AUC0-4 ↑ 19 ± 27%
(range: -11% to 74%)
|Mycophenolate Mofetil (MMF) 1.5 g single dose||IV ganciclovir 5 mg/kg single dose||12||No PK interaction observed (patients with normal renal function)|
|Didanosine 200 mg every 12 hours when administered 2 hours prior to or concurrent with ganciclovir||1000 mg every 8 hours||12||AUC0-12 ↑111 ± 114%
(range: 10% to 493%)
|Didanosine 200 mg every 12 hours||IV ganciclovir 5 mg/kg twice daily||11||AUC0-12 ↑70 ± 40%
(range: 3% to 121%)
|Cmax↑49 ± 48%
(range: -28% to 125%)
|Didanosine 200 mg every 12 hours||IV ganciclovir 5 mg/kg once daily||11||AUC0-12 ↑50 ± 26%
(range: 22% to 110%)
|Cmax ↑36 ± 36%
(range: -27% to 94%)
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||Increase (12%) in Cmin|
Other potential drug interactions
Since ganciclovir is excreted through the kidney via glomerular filtration and active secretion [see Pharmacokinetics (12.3)], coadministration of valganciclovir with antiretroviral drugs that share the tubular secretion pathway, such as nucleos(t)ide reverse transcriptase inhibitors, may change the plasma concentrations of valganciclovir and/or the coadministered drug.
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% (EC50), vary greatly depending upon a number of factors including the assay used. Thus, the reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 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 (CC50) 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 [CC50 value = 2.7 to 12 µM (0.69 to 3.06 mcg/mL)].
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.
|Note: Many additional pathways to ganciclovir resistance likely exist|
|pUL97||L405P, A440V, M460I/V/T, V466G/M, C518Y, H520Q, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, A613V|
|pUL54||E315D, N408D/K/S, F412C/L/S, D413A/E, L501F/I, T503I, K513E/N/R, I521T, P522A/L/S, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987G|
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.
|Cross-resistant to cidofovir||D301N, N408D/K, N410K, F412C/L/S/V, D413E, L501I, T503I, K513E/N, L516R, I521T, P522S/A, L545S/W, Q578H, D588N, I726T/V, E756K, V812L, T813S, A834P, G841A, del 981-982, A987G|
|Cross-resistant to foscarnet||F412C, Q578H/L, D588N, E756K, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A, del 981-982|
Long-term carcinogenicity studies have not been conducted with VALCYTE. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen.
Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1× and 1.4×, 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 1.7× 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 0.1× 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.
Induction Therapy of CMV Retinitis: In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either VALCYTE tablets (900 mg twice daily for 21 days, then 900 mg once daily for 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 log10, and the median CD4 cell count was 23 cells/mm3. 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.
|Intravenous Ganciclovir||VALCYTE Tablets|
|Determination of CMV retinitis progression at Week 4||N=80||N=80|
|Discontinuations due to Adverse Events||1||2|
|Failed to return||1||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 VALCYTE tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label VALCYTE tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg VALCYTE tablets once daily and 5 mg per kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following VALCYTE tablets administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration [see Figure 1 in Clinical Pharmacology (12.3)]. Therefore, use of VALCYTE 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 VALCYTE: 1 oral ganciclovir) to receive either VALCYTE 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 VALCYTE tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the VALCYTE group compared with the ganciclovir group. These results are summarized in Table 19.
Mortality at six months was 3.7% (9/244) in the VALCYTE group and 1.6% (2/126) in the oral ganciclovir group.
|CMV Disease*||Tissue-Invasive CMV Disease||CMV Syndrome†|
|GCV = oral ganciclovir; VGCV = valganciclovir|
(22 / 118)
(7 / 59)
(16 / 118)
(2 / 59)
(6 / 118)
(5 / 59)
(5 / 81)
(9 / 39)
(1 / 81)
(2 / 39)
(4 / 81)
(7 / 39)
(2 / 35)
(2 / 21)
(0 / 35)
(1 / 21)
(2 / 35)
(1 / 21)
|Kidney / Pancreas
(0 / 5)
(1 / 6)
(0 / 5)
(1 / 6)
(0 / 5)
(0 / 6)
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 VALCYTE CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive VALCYTE tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with VALCYTE until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 20.
|CMV Disease*||Tissue-Invasive CMV Disease||CMV Syndrome†|
|VGCV = valganciclovir.|
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.
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 VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until a maximum of 100 days post-transplant. The daily doses of VALCYTE 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 VALCYTE 900 mg once daily, but were within the range considered safe and effective in adults [see Clinical Pharmacology (12.3)]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first six months post-transplantation.
Prevention of CMV in Pediatric Kidney Transplantation: Fifty-seven children, 1 to 16 years of age, who had a renal transplant and were at risk for developing CMV disease, were enrolled in an open-label tolerability study of oral VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until a maximum of 200 days post-transplant. The daily doses of VALCYTE were calculated at each study visit based on body surface area and a modified creatinine clearance [see Dosage and Administration (2.3)]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first 12 months post-transplantation.
1. Brion, L.P., Fleischman, A.R., McCarton, C., Schwartz, G.J. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J of Ped 1986: 109(4): 698-707.
2. NIOSH . NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor T.H., MacKenzie B.A., DeBord D.G., Trout D.B., O'Callaghan J.P., Cincinnati, O.H.: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).
VALCYTE tablets: Supplied as 450 mg, pink, convex oval tablets with "VGC" on one side and "450" on the other side. Each tablet contains valganciclovir HCl equivalent to 450 mg valganciclovir. VALCYTE is supplied in bottles of 60 tablets (NDC 0004-0038-22).
VALCYTE for oral solution: Supplied as a white to slightly yellow powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Each bottle can deliver up to a total of 88 mL of solution. Each bottle is supplied with a bottle adapter and 2 oral dispensers (NDC 0004-0039-09).
Prior to dispensing to the patient, VALCYTE for oral solution must be prepared by the pharmacist [see Dosage and Administration (2.4)].
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Serious Adverse Reactions
Inform patients that VALCYTE may cause granulocytopenia (neutropenia), anemia, thrombocytopenia and elevated creatinine levels and that dose modification or discontinuation of dosing may be required. Complete blood counts, platelet counts, and creatinine levels should be performed frequently during treatment [see Warnings and Precautions (5.1)].
Pregnancy and Contraception
Inform females of reproductive potential that VALCYTE causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with VALCYTE. Similarly, advise males to practice barrier contraception during and for at least 90 days following treatment with VALCYTE [see Use in Specific Populations (8.1, 8.3)].
Advise patients that VALCYTE is considered a potential carcinogen [see Nonclinical Toxicity (13.1)].
Advise mothers not to breast-feed if they are receiving VALCYTE because of the potential for hematologic toxicity and cancer in nursing infants, and because HIV can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].
Impairment of Cognitive Ability
Inform patients that tasks requiring alertness may be affected including the patient's ability to drive and operate machinery as convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of VALCYTE [see Adverse Reactions (6.1)].
Use in Patients with CMV Retinitis
Inform patients that VALCYTE is not a cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with VALCYTE. Some patients will require more frequent follow-up.
Inform adult patients that they should use VALCYTE tablets, not VALCYTE for oral solution [see Dosage and Administration (2.1)].
Inform patients to take VALCYTE with food to maximize bioavailability.
What is VALCYTE?
VALCYTE is a prescription antiviral medicine.
In adults, VALCYTE tablets are used:
In children, VALCYTE tablets or oral solution are used:
VALCYTE does not cure CMV retinitis. You may still get retinitis or worsening of retinitis during or after treatment with VALCYTE. It is important to stay under a healthcare provider's care and have your eyes checked every 4 to 6 weeks during treatment with VALCYTE.
Who should not take VALCYTE?
Do not take VALCYTE if you are allergic to any of its ingredients or if you have ever had a serious allergic reaction to ganciclovir capsules or Cytovene-IV. Symptoms of an allergic reaction to VALCYTE may include: sudden trouble breathing, wheezing, hives all over your body, swelling around your mouth, or feeling anxious.
See the end of this leaflet for a list of the ingredients in VALCYTE.
What should I tell my healthcare provider before taking VALCYTE?
Before taking VALCYTE, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
VALCYTE and other medicines may affect each other and cause serious side effects. Keep a list of your medicines to show your healthcare provider and pharmacist.
How should I take VALCYTE?
Talk to your healthcare provider, nurse or pharmacist if you have questions about your medicine.
What should I avoid while taking VALCYTE?
What are the possible side effects of VALCYTE?
VALCYTE may cause serious side effects, including:
Common side effects of VALCYTE in adults and children include:
Other common side effects in children include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of VALCYTE. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store VALCYTE?
General information about the safe and effective use of VALCYTE
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VALCYTE for a condition for which it was not prescribed. Do not give VALCYTE to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about VALCYTE. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VALCYTE that is written for health professionals.
For more information about VALCYTE go to www.VALCYTE.com or call 1-888-835-2555.
Active ingredient: valganciclovir hydrochloride
Inactive ingredients for Tablets: microcrystalline cellulose, povidone K-30, crospovidone, and stearic acid. The film-coating applied to the tablets contains Opadry Pink®.
Inactive ingredients for Oral Solution: sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring
for oral solution
How do I give VALCYTE for oral solution?
This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration
VALCYTE is a registered trademark of Hoffmann-La Roche Inc.
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
Revised: April 2015
© 2015 Genentech, Inc. All rights reserved.
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):
(valganciclovir HCl tablets)
equivalent to 450 mg valganciclovir
DO NOT BREAK OR CRUSH TABLETS
for oral solution
50 mg/1 mL
Each mL of constituted
oral solution contains
50 mg valganciclovir
100 mL (3.4 fl oz)
valganciclovir hydrochloride tablet, film coated
|Marketing Category||Application Number or Monograph Citation||Marketing Start Date||Marketing End Date|
valganciclovir hydrochloride powder, for solution
|Marketing Category||Application Number or Monograph Citation||Marketing Start Date||Marketing End Date|
|Labeler - Genentech, Inc. (080129000)|
|F. Hoffmann-La Roche Ltd||482242971||API MANUFACTURE, API MANUFACTURE|
Revised: 04/2015 Genentech, Inc.