VALGANCICLOVIR HYDROCHLORIDE

Valganciclovir HCl Tablets, USP 450 mg

1 INDICATIONS AND USAGE

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)] .

Prevention of CMV Disease: Valganciclovir tablets are indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)] .

1.2 Pediatric Patients

Prevention of CMV Disease: Valganciclovir tablets are 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)] .

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with valganciclovir hydrochloride or ganciclovir. Valganciclovir hydrochloride 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 hydrochloride should also be used with caution in patients with pre-existing cytopenias and in patients 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. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving valganciclovir hydrochloride [see Adverse Reactions (6.1)] , complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and 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 hydrochloride because of increased plasma concentrations of ganciclovir after valganciclovir hydrochloride administration [see Clinical Pharmacology (12.3)] .

5.2 Acute Renal Failure

Acute renal failure may occur in:

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

5.3 Impairment of Fertility

Based on animal data and limited human data, valganciclovir hydrochloride 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 fertility may be impaired with use of valganciclovir hydrochloride Based on animal data and limited human data, valganciclovir hydrochloride 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 hydrochloride [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

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

5.5 Mutagenesis and Carcinogenesis

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

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Hematologic Toxicity [see Warnings and Precautions (5.1)].
• Acute Renal Failure [see Warnings and Precautions (5.2)].
• Impairment of Fertility [see Warnings and Precautions (5.3)] .
• Fetal Toxicity [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].

The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with valganciclovir tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with valganciclovir for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse reactions known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir hydrochloride.

Adverse Reactions in Adults:

Treatment of CMV Retinitis in AIDS Patients: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions reported by patients receiving valganciclovir tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), and headache (9%, 5%). The incidence of adverse reactions was similar between the group who received valganciclovir tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse reactions and laboratory abnormalities are available for 370 patients who received maintenance therapy with valganciclovir tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show pooled selected adverse reactions and abnormal laboratory values from these patients.

Table 3 Pooled Selected Adverse Reactions Reported in greater than or equal to 5% of Patients who Received Valganciclovir Tablets Maintenance Therapy for CMV Retinitis
	Patients with CMV Retinitis
Adverse Reactions according to Body System	Valganciclovir Tablets**(N=370)** %
** Gastrointestinal system** Diarrhea Nausea Vomiting Abdominal pain	41 30 21 15
General disorders and administrative site conditions Pyrexia	31
Nervous system disorders Headache Insomnia Neuropathy peripheral Paresthesia	22 16 9 8
Eye disorders Retinal detachment	15

Table 4 Pooled Selected Laboratory Abnormalities Reported in Patients Who Received Valganciclovir Tablets Maintenance Therapy for the Treatment of CMV Retinitis
	Patients with CMV Retinitis
Laboratory Abnormalities	Valganciclovir Tablets (N=370) %
Neutropenia: ANC/µL < 500 500 – < 750 750 – < 1000	19 17 17
Anemia: Hemoglobin g/dL < 6.5 6.5 – < 8.0 8.0 - < 9.5	7 13 16
Thrombocytopenia: Platelets/µL < 25000 25000 – < 50000 50000 – < 100000	4 6 22
Serum Creatinine: mg/dL 2.5 1.5 – 2.5	3 12

Prevention of CMV Disease in Solid Organ Transplant Patients: Table 5** **shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received valganciclovir tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse reactions were of mild or moderate intensity.

Table 5 Percentage of Selected Grades 1 to 4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients From a Study of Solid Organ Transplant Patients
Adverse Reactions	Valganciclovir Tablets (N=244) %	Oral Ganciclovir (N=126) %
Gastrointestinal disorders
Diarrhea	30	29
Nausea	23	23
Vomiting	16	14
Nervous system disorders
Tremors	28	25
Headache	22	27
Insomnia	20	16
General disorders and administration site conditions
Pyrexia	13	14

Table 6 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either valganciclovir once daily starting within 10 days post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily until Day 200 post-transplant. The overall safety profile of valganciclovir did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients.

Table 6 Percentage of Selected Grades 1 to 4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients
Adverse Reactions	Valganciclovir Tablets Day 100 Post-transplant (N=164) %	Valganciclovir Tablets Day 200 Post-transplant (N=156) %
Gastrointestinal disorders
Diarrhea	26	31
Nausea	11	11
Vomiting	3	6
Nervous system disorders
Tremors	12	17
Headache	10	6
Insomnia	7	6
General disorders and administration site conditions
Pyrexia	12	9

Table 7 and Table 8 show selected laboratory abnormalities reported with valganciclovir tablets in two trials in solid organ transplant patients.

Table 7 Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients*
Laboratory Abnormalities	Valganciclovir Tablets (N=244) %	Ganciclovir Capsules (N=126) %
Neutropenia: ANC/µL < 500 500 – < 750 750 – < 1000	5 3 5	3 2 2
Anemia: Hemoglobin g/dL < 6.5 6.5 – < 8.0 8.0 – < 9.5	1 5 31	2 7 25
Thrombocytopenia: Platelets/µL < 25000 25000 – < 50000 50000 – < 100000	0 1 18	2 3 21
Serum Creatinine: mg/dL 2.5 1.5 – 2.5	14 45	21 47
Laboratory abnormalities are those reported by investigators.

Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients*
Laboratory Abnormalities	Valganciclovir Tablets Day 100 Post-transplant (N=164) %	Valganciclovir Tablets Day 200 Post-transplant (N=156) %
Neutropenia: ANC/µL
< 500	9	10
500 – < 750	6	6
750 – < 1000	7	5
Anemia: Hemoglobin g/dL
< 6.5	0	1
6.5 – < 8.0	5	1
8.0 - < 9.5	17	15
Thrombocytopenia: Platelets/µL
< 25000	0	0
25000 – < 50000	1	0
50000 – < 100000	7	3
Serum Creatinine: mg/dL 2.5 1.5 – 2.5	17 50	14 48
Laboratory abnormalities are those reported by investigators.

Other adverse drug reactions from valganciclovir hydrochloride in clinical trials in CMV retinitis and solid organ transplant patients

Other adverse drug reactions with valganciclovir hydrochloride in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in at least 5% of patients are listed below.

Eye disorders: retinal detachment, eye pain

Gastrointestinal disorders: dyspepsia, constipation, abdominal distention, mouth ulceration

General disorders and administration site conditions: fatigue, pain, malaise, asthenia, chills, peripheral edema

Hepatobiliary disorders: hepatic function abnormal

Infections and infestations: candida infections including oral candidiasis, upper respiratory tract infection, influenza, urinary tract infection, pharyngitis/nasopharyngitis, postoperative wound infection

Injury, poisoning, and procedural complications: postoperative complications, wound secretion

Metabolic and nutrition disorders: decreased appetite, hyperkalemia, hypophosphatemia, weight decreased

Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms

Nervous system disorders: insomnia, neuropathy peripheral, dizziness

Psychiatric disorders: depression, anxiety

Renal and urinary disorders: renal impairment, creatinine clearance renal decreased, blood creatinine increased, hematuria

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissues disorders: dermatitis, night sweats, pruritus

Vascular disorders: hypotension

Other adverse reactions with valganciclovir hydrochloride in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in less than 5% of patients are listed below.

Blood and lymphatic disorders: febrile neutropenia, pancytopenia, bone marrow failure (including aplastic anemia)

Cardiovascular disorders: arrhythmia

Ear and labyrinth disorders: deafness

Eye disorders: macular edema

Gastrointestinal disorders: pancreatitis

Hemorrhage: potentially life-threatening bleeding associated with thrombocytopenia

Immune system disorders: hypersensitivity

Infections and infestations: cellulitis, sepsis

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

Investigations: aspartate aminotransferase increased, alanine aminotransferase increased

Musculoskeletal and connective tissue disorders: limb pain

Nervous system disorders: seizure, dysguesia (taste disturbance)

Psychiatric disorders: confusional state, agitation, psychotic disorder, hallucinations

Renal and urinary disorders: renal failure

Adverse Reactions in Pediatric Patients:

Valganciclovir for oral solution and tablets have been studied in 179 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 3 weeks to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 200 days [see Use in Specific Populations (8.4), Clinical Studies (14.2)] .

Prevention of CMV Disease in Pediatric Solid Organ Transplant Patients: The most frequently reported adverse reactions (greater than 10% of patients), regardless of seriousness, in pediatric solid organ transplant patients taking valganciclovir hydrochloride until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation and nausea. The most frequently reported adverse reactions (greater than 10% of patients) in pediatric kidney transplant patients treated with valganciclovir until Day 200 post-transplant were upper respiratory tract infection, urinary tract infection, diarrhea, leukopenia, neutropenia, headache, abdominal pain, tremor, pyrexia, anemia, blood creatinine increased, vomiting, and hematuria.

In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse reactions, and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. Neutropenia was reported at a higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.

The overall safety profile of valganciclovir was similar with the extension of prophylaxis until Day 200 post-transplant in high risk pediatric kidney transplant patients. However, the incidence of severe neutropenia (ANC < 500/μL) was higher in pediatric kidney transplant patients treated with valganciclovir until Day 200 (17/57, 30%) compared to pediatric kidney transplant patients treated until Day 100 (3/63, 5%). There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated 100 or 200 days with valganciclovir.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of valganciclovir hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As valganciclovir hydrochloride is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir.

- Anaphylactic reaction

- Agranulocytosis

- Granulocytopenia

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with valganciclovir hydrochloride. 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 times and 1.4 times, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose, there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans.

Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay.

Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see Warnings and Precautions (5.3)] . Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7 times 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 times 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.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

---

** Serious Adverse Reactions**

---

Inform patients that valganciclovir hydrochloride 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 monitored frequently during treatment [see Warnings and Precautions (5.1)].

---

** Pregnancy and Contraception**

---

Inform females of reproductive potential that valganciclovir hydrochloride causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with valganciclovir hydrochloride. Similarly, advise males to use condoms during and for at least 90 days following treatment with valganciclovir hydrochloride [see Use in Specific Populations (8.1, 8.3)] .

---

** Carcinogenicity**

---

Advise patients that valganciclovir hydrochloride is considered a potential carcinogen [see Nonclinical Toxicity (13.1)] .

---

** Lactation**

---

Advise mothers not to breast-feed if they are receiving valganciclovir hydrochloride 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)].

---

** Infertility**

---

Advise patients that valganciclovir hydrochloride may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)] .

---

** Impairment of Cognitive Ability**

---

Inform patients that tasks requiring alertness may be affected including the patient’s ability to drive and operate machinery as seizures, dizziness, and/or confusion have been reported with the use of valganciclovir hydrochloride [see Adverse Reactions (6.1)] .

---

** Use in Patients with CMV Retinitis**

---

Inform patients that valganciclovir hydrochloride 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 valganciclovir hydrochloride. Some patients will require more frequent follow- up.

---

** Administration**

---

Inform adult patients that they should use valganciclovir tablets, not valganciclovir for oral solution [see Dosage and Administration (2.1)] .

Inform patients to take valganciclovir hydrochloride with food to maximize bioavailability.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

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

2.2 Recommended Dosage in Adult Patients with Normal Renal Function

For dosage recommendations in adult patients with renal impairment [see Dosage and Administration (2.5)] .

Treatment of CMV Retinitis:

• Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice a day for 21 days.
• Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day.

Prevention of CMV Disease:

• For adult patients who have received a heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 100 days post-transplantation.
• For adult patients who have received a kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 200 days post-transplantation.

2.3 Recommended Dosage in Pediatric Patients

Prevention of CMV Disease in Pediatric Kidney Transplant Patients: For pediatric kidney transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of post-transplantation until 200 days post-transplantation.

Prevention of CMV Disease in Pediatric Heart Transplant Patients: For pediatric heart transplant patients 1 month to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of transplantation until 100 days post-transplantation.

The recommended once daily dosage of valganciclovir tablets are based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:

Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m 2, then a maximum value of 150 mL/min/1.73m 2 should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.


Table 1 k Values According to Pediatric Patient Age*

*The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used 1.
** k value**	** Pediatric Patient Age**
0.33	Infants less than 1 year of age with low birth weight for gestational age
0.45	Infants less than 1 year of age with birth weight appropriate for gestational age
0.45	Children aged 1 to less than 2 years
0.55	Boys aged 2 to less than 13 years Girls aged 2 to less than 16 years
0.7	Boys aged 13 to 16 years

Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.

All calculated doses should be rounded to the nearest 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.

2.5 Dosage Recommendation for Adult Patients with Renal Impairment

Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), a dose recommendation for valganciclovir tablets cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].

Table 2 Dosage Recommendations for Adult Patients with Impaired Renal Function

Valganciclovir Tablets 450 mg
CrCl* (mL/min)	Induction Dose	Maintenance/Prevention Dose
*An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:
≥ 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
< 10 (on hemodialysis)	not recommended	not recommended

(140 – age [years]) x (body weight [kg])

For males = –––––––––––––––––––––––––––––––––

(72) x (serum creatinine [mg/dL])

For females = 0.85 x male value

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3)] .

2.6 Handling and Disposal

Caution should be exercised in the handling of valganciclovir tablets. 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 (5.4, 5.5)] . 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.