VALGANCICLOVIR: 7,913 Adverse Event Reports & Safety Profile

Valganciclovir for oral solution contains valganciclovir hydrochloride, USP (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. Valganciclovir is 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 Valganciclovir for oral solution are sodium benzoate, tartaric acid, povidone, sodium saccharin, mannitol and fruity flavoring (banana, peach and pineapple). Composition of banana, peach and pineapple flavor powders: Maltodextrin, silicon dioxide, gum arabic (banana flavor powder and pineapple flavor powder), starch sodium octenyl succinate, triacetin and alpha-tocopherol (peach flavor powder). Valganciclovir hydrochloride, USP is a white to off-white crystalline powder with a molecular formula of C 14 H 22 N 6 O 5 ·HCl and a molecular weight of 390.82. The chemical name for valganciclovir hydrochloride is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir hydrochloride 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 hydrochloride is 7.6. The chemical structure of valganciclovir HCl is: All doses in this insert are specified in terms of valganciclovir. structure

AND USAGE Valganciclovir hydrochloride is a deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for: Adult Patients ( 1.1 )

• Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).
• Prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk.

Pediatric

Patients ( 1.2 )

• Prevention of CMV disease in kidney and heart transplant patients at high risk.

1.1 Adult Patients Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir hydrochloride is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>. Prevention of CMV Disease: Valganciclovir hydrochloride 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-]) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

1.2 Pediatric Patients Prevention of CMV Disease: Valganciclovir hydrochloride 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>.

1.1 Adult Patients Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir hydrochloride is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>. Prevention of CMV Disease: Valganciclovir hydrochloride 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-]) <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

AND ADMINISTRATION N/A 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) Valganciclovir hydrochloride for oral solution should be taken with food. ( 2.1 , 12.3 ) Valganciclovir hydrochloride tablets should not be broken or crushed. ( 2.6 ) Adult patients should use Valganciclovir hydrochloride tablets, not Valganciclovir hydrochloride for oral solution. ( 2.1 ) Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis a dose recommendation cannot be given. ( 2.5 , 8.6 , 12.3 )

2.1 General Dosing Information

• Adult patients should use Valganciclovir hydrochloride tablets, not Valganciclovir hydrochloride for oral solution.
• Valganciclovir hydrochloride for oral solution should be taken with food [see Clinical Pharmacology (12.3)] .
• Valganciclovir hydrochloride for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)] .

2.2 Recommended Dosage in Adult Patients with Normal Renal Function For dosage recommendations in adult patients with renal impairment <span class="opacity-50 text-xs">[see Dosage and Administration (2.5)]</span>. 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 hydrochloride is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below: Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m 2 , then a maximum value of 150 mL/min/1.73m 2 should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.

Table

1 k Values According to Pediatric Patient Age* k value Pediatric Patient Age

0.33 Infants less than 1 year of age with low birth weight for gestational age

0.45 Infants less than 1 year of age with birth weight appropriate for gestational age

0.45 Children aged 1 to less than 2 years

0.55 Boys aged 2 to less than 13 years Girls aged 2 to less than 16 years

0.7 Boys aged 13 to 16 years *The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used 1 . Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period. All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. The oral dispenser is graduated in 0.5 mL increments. A 50 mg dose is equivalent to 1 mL. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valganciclovir hydrochloride for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valganciclovir hydrochloride 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 hydrochloride tablets, pediatric patients should be assessed for the ability to swallow tablets. figure-1

2.4 Preparation of Valganciclovir for oral solution Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Prior to dispensing to the patient, Valganciclovir hydrochloride for oral solution must be prepared by the pharmacist as follows <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16)]</span>:

• Measure 91 mL of purified water in a graduated cylinder.
• Shake the Valganciclovir bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. This prepared solution contains 50 mg of valganciclovir free base per 1 mL.
• Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.
• Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.
• Store constituted oral solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.
• Write the discard date of the constituted oral solution on the bottle label. The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient [see Patient Counseling Information (17)] .

2.5 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 hydrochloride tablets cannot be given <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]</span>.

Table

2 Dosage Recommendations for Adult Patients with Impaired Renal Function *An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas: For males = (140 – age [years]) x (body weight [kg]) ———————————————— (72) x (serum creatinine [mg/dL]) For females = 0.85 x male value Valganciclovir hydrochloride 450 mg Tablets CrCl* (mL/min)

Induction Dose

Maintenance/ Prevention Dose ≥ 60 900 mg twice daily 900 mg once daily 40 to 59 450 mg twice daily 450 mg once daily 25 to 39 450 mg once daily 450 mg every 2 days 10 to 24 450 mg every 2 days 450 mg twice weekly < 10 (on hemodialysis) 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)].

2.6 Handling and Disposal Caution should be exercised in the handling of valganciclovir hydrochloride tablets and valganciclovir 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4, 5.5)]</span> . 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 valganciclovir hydrochloride according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity) 2 .

Valganciclovir for oral solution 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 )]. Hypersensitivity to valganciclovir or ganciclovir. ( 4 )

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 hydrochloride 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 hydrochloride for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. Adult patients: Most common adverse reactions and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. ( 6.1 ) Pediatric patients: Most common adverse reactions and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc., at 1-877-770-3183 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse reactions known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir.

Adverse

Reactions in Adults: Treatment of CMV Retinitis in AIDS Patients: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions reported by patients receiving valganciclovir hydrochloride 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 hydrochloride tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir hydrochloride 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 hydrochloride tablets 900 mg once daily in two open-label clinical trials.

Approximately

252 (68%) of these patients received valganciclovir hydrochloride 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 Hydrochloride Tablets Maintenance Therapy for CMV Retinitis Patients with CMV Retinitis Adverse Reactions according to Body System Valganciclovir Hydrochloride 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 Hydrochloride Tablets Maintenance Therapy for the Treatment of CMV Retinitis Patients with CMV Retinitis Laboratory Abnormalities Valganciclovir Hydrochloride Tablets (N=370) % Neutropenia: ANC/μL < 500 500 to < 750 750 to < 1000 19 17 17 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5 7 13 16 Thrombocytopenia: Platelets/μL < 25000 25000 to < 50000 50000 to < 100000 4 6 22 Serum Creatinine: mg/dL > 2.5 > 1.5 to 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 hydrochloride 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 Hydrochloride 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 hydrochloride 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 Hydrochloride Tablets Day 100 Post-transplant (N=164) % Valganciclovir Hydrochloride 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 hydrochloride 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 Hydrochloride Tablets (N=244) % Ganciclovir Capsules (N=126) % Neutropenia: ANC/μL < 500 500 to < 750 750 to < 1000 5 3 5 3 2 2 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5 1 5 31 2 7 25 Thrombocytopenia: Platelets/mL < 25000 25000 to < 50000 50000 to < 100000 0 1 18 2 3 21 Serum Creatinine: mg/dL > 2.5 > 1.5 to 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 Hydrochloride Tablets Day 100 Post-transplant (N=164) % Valganciclovir Hydrochloride Tablets Day 200 Post- transplant (N=156) % Neutropenia: ANC/µL < 500 500 to < 750 750 to < 1000 9 6 7 10 6 5 Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5 0 5 17 1 1 15 Thrombocytopenia: Platelets/µL < 25000 25000 to < 50000 50000 to < 100000 0 1 7 0 0 3 Serum Creatinine: mg/dL > 2.5 > 1.5 to 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 hydrochloride 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 for oral solution until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation and nausea. The most frequently reported adverse reactions (greater than 10% of patients) in pediatric kidney transplant patients treated with valganciclovir until Day 200 post-transplant were upper respiratory tract infection, urinary tract infection, diarrhea, leukopenia, neutropenia, headache, abdominal pain, tremor, pyrexia, anemia, blood creatinine increased, vomiting, and hematuria. In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse reactions, and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4) , Clinical Studies (14.2) ]. Neutropenia was reported at a higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.

Adverse

Reactions in Pediatric Patients: Valganciclovir hydrochloride 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 for oral solution until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation and nausea. The most frequently reported adverse reactions (greater than 10% of patients) in pediatric kidney transplant patients treated with valganciclovir until Day 200 post-transplant were upper respiratory tract infection, urinary tract infection, diarrhea, leukopenia, neutropenia, headache, abdominal pain, tremor, pyrexia, anemia, blood creatinine increased, vomiting, and hematuria. In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse reactions, and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4) , Clinical Studies (14.2) ]. Neutropenia was reported at a higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population. The overall safety profile of Valganciclovir hydrochloride 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 hydrochloride 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 hydrochloride.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Valganciclovir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

As

Valganciclovir is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir. – Anaphylactic reaction – Agranulocytosis – Granulocytopenia In general, the adverse reactions reported during the postmarketing use of Valganciclovir were similar to those identified during the clinical trials.

AND PRECAUTIONS

• Hematologic toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have occurred with the use of valganciclovir tablets or ganciclovir. Avoid valganciclovir tablets use if absolute neutrophil count is less than 500 cells/µL, platelet count is less than 25,000/µL, or hemoglobin is less than 8 g/dL. Use with caution in pre-existing cytopenias and when receiving myelosuppressive drugs or irradiation. Monitor with frequent testing of platelet and complete blood counts ( 5.1 ).
• Impairment of fertility: Based on animal studies, valganciclovir tablets may cause temporary or permanent inhibition of spermatogenesis ( 5.2 ).
• Fetal toxicity: Based on animal studies, valganciclovir tablets may cause fetal harm. Females of reproductive potential should use effective contraception during and following treatment and males should practice barrier contraception during and following treatment (5.3 ).
• Mutagenicity and carcinogenicity: Based on animal studies, valganciclovir tablets are potentially mutagenic and carcinogenic ( 5.4 ).
• Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function ( 2.5 , 5.5 , 8.5 , 8.6 , 12.3 ). 5.1Hematologic Toxicity Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with valganciclovir tablets or ganciclovir. Valganciclovir tablets 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 tablets should also be used with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving valganciclovir tablets [see Adverse Reactions ( 6.1 )], complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/μL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to valganciclovir tablets, because of increased plasma concentrations of ganciclovir after valganciclovir tablets administration [see Clinical Pharmacology ( 12.3 )].

5.2 Impairment of Fertility Based on animal data with ganciclovir, valganciclovir tablets 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 tablets <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1, 8.3 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.3 Fetal Toxicity Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2-times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, valganciclovir has the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir tablets and in females with male partners taking valganciclovir tablets. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir tablets. Similarly, males should be advised to practice barrier contraception during and for at least 90 days following treatment with valganciclovir tablets <span class="opacity-50 text-xs">[see Dosage and Administration (2.6), Use in Specific Populations ( 8.1, 8.3 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.4 Mutagenesis and Carcinogenesis Animal data indicate that ganciclovir is mutagenic and carcinogenic. Valganciclovir tablets should therefore be considered a potential carcinogen in humans <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.5 Acute Renal Failure Acute renal failure may occur in:

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

INTERACTIONS 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. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of VALCYTE and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9 .

Table

9 Established and Other Potentially Significant Drug Interactions with Ganciclovir Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment Imipenem-cilastatin Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. Cyclosporine or amphotericin B Unknown Monitor renal function when VALCYTE is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2) ]. Mycophenolate mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity. Other drugs associated with myelosuppression or nephrotoxicity (e.g., adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine, and zidovudine)

Unknown

Because of potential for higher toxicity, coadministration with VALCYTE should be considered only if the potential benefits are judged to outweigh the risks. Didanosine ↔ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis) Probenecid ↑ Ganciclovir VALCYTE dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. ( 7 ) Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. ( 5.2 , 7 ) Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. ( 7 ) Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. ( 7 ) Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). ( 7 ) Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. ( 7 )

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) ].

Table

15 and Table 16 provide a listing of established drug interaction studies with ganciclovir.

Table

15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table

15 Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK)

Parameter

Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function)

Trimethoprim

200 mg once daily 1000 mg every 8 hours 12 No effect on ganciclovir PK parameters observed Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 5 mg/kg IV twice daily 11 No effect on ganciclovir PK parameters observed 5 mg/kg IV once daily 11 No effect on ganciclovir PK parameters observed Probenecid 500 mg every 6 hours 1000 mg every 8 hours 10 AUC ↑ 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance ↓ 22 ± 20% (range: -54% to -4%)

Table

16 Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered Drug Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK)

Parameter

Oral cyclosporine at therapeutic doses 5 mg/kg infused over 1 hour every 12 hours 93 In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations. Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No PK interaction observed (patients with normal renal function)

Trimethoprim

200 mg once daily 1000 mg every 8 hours 12 No effect on trimethoprim PK parameters observed Didanosine 200 mg every 12 hours 5 mg/kg IV twice daily 11 AUC 0-12 ↑70 ± 40% (range: 3% to 121%) C max ↑49 ± 48% (range: -28% to 125%)

Didanosine

200 mg every 12 hours 5 mg/kg IV once daily 11 AUC 0-12 ↑50 ± 26% (range: 22% to 110%) C max ↑36 ± 36% (range: -27% to 94%)