1 INDICATIONS AND USAGE Valganciclovir Tablets, USP are 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 Tablets, USP are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [ see Clinical Studies (14.1) ].

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

1.2 Pediatric Patients Prevention of CMV Disease : Valganciclovir Tablets, USP are indicated for the prevention of CMV disease in 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) ].

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.

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 AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com 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 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 the 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 41 30 21 15 Nausea Vomiting Abdominal pain General disorders and administrative site conditions Pyrexia Nervous system disorders Headache Insomnia Neuropathy peripheral Paresthesia 31 22 16 9 8 Eye disorders 15 Retinal detachment 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 19 17 17 500 – < 750 750 – < 1000 Anemia: Hemoglobin g/dL < 6.5 7 13 16 6.5 – < 8.0 8.0 – < 9.5 Thrombocytopenia: Platelets/µL < 25000 4 6 22 25000 – < 50000 50000 – < 100000 Serum Creatinine: mg/dL > 2.5 3 12 > 1.5 – 2.5 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 1-4 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 1-4 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 5 3 5 3 2 2 500 - < 750 750 - < 1000 Anemia: Hemoglobin g/dL < 6.5 1 2 6.5 – < 8.0 5 31 7 25 8.0 – < 9.5 Thrombocytopenia: Platelets/µL < 25000 0 1 18 2 3 21 25000 – < 50000 50000 – < 100000 Serum Creatinine: mg/dL 14 45 > 2.5 21 47 > 1.5 – 2.5 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 9 6 7 < 500 10 6 5 500 – < 750 750 – < 1000 Anemia: Hemoglobin g/dL < 6.5 0 5 17 1 1 15 6.5 – < 8.0 8.0 – < 9.5 Thrombocytopenia: Platelets/µL < 25000 0 1 7 0 0 3 25000 – < 50000 50000 – < 100000 Serum Creatinine: mg/dL > 2.5 17 50 14 48 > 1.5 – 2.5 Other adverse drug reactions from valganciclovir in clinical trials in CMV Retinitis and solid organ transplant patients Other adverse drug reactions with valganciclovir 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 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 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.

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.

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

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