1 INDICATIONS & USAGE Valganciclovir tablets, USP are a cytomegalovirus (CMV) nucleoside analogue 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 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 heart transplant patients (4 month to 16 years of age) at high risk [see Clinical Studies ( 14.2 )].

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC' s VALCYTE (valganciclovir hydrochloride) tablets.

However, due to Roche Palo Alto LLC' s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6 ADVERSE REACTIONS The following serious adverse events are discussed in greater detail in other sections of the labeling: • Hematologic toxicity [see Boxed Warning, Warnings and Precautions ( 5.1 )].

• Acute renal failure [see Warnings and Precautions ( 5.5 )].

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 valganciclovir 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 valganciclovir tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and head ache.

• Adult patients: Most common adverse events and laboratory abnormalities (reported in at least one indication by greater than or equal to 20% of patients) are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting ( 6.1 ).

• Pediatric patients: Most common adverse events and laboratory abnormalities (reported in greater than or equal to 20% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc.

at 1-855-361-3993 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 event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration.

Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir tablets.

Adverse Events in Adults: Treatment of CMV Retinitis in AIDS Patients : In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving valganciclovir tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%).

The incidence of adverse events was similar between the group who received valganciclovir tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir.

The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir tablets compared with 13% for patients receiving intravenous ganciclovir.

Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group.

Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with valganciclovir tablets 900 mg once daily in two open-label clinical trials.

Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months).

Table 3 and Table 4 show the pooled adverse event data and abnormal laboratory values from these patients.

Table 3 Pooled Selected Adverse Events Reported in greater than or equal to 5% of Patients who Received Valganciclovir Tablets Maintenance Therapy for CMV Retinitis Patients with CMV Retinitis Adverse Events According to Body System Valganciclovir Tablets (N=370) % Gastrointestinal system Diarrhea 41 Nausea 30 Vomiting 21 Abdominal pain 15 Body as a Whole Pyrexia 31 Headache 22 Central and peripheral nervous system Insomnia 16 Peripheral neuropathy 9 Paresthesia 8 Special senses Retinal detachment 15 Table 4 Pooled 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 19 500 – < 750 17 750 – <1000 17 Anemia: Hemoglobin g/dL < 6.5 7 6.5 – < 8 13 8 – <9.5 16 Thrombocytopenia: Platelets/µL <25000 4 25000 – < 50000 6 50000 – < 100000 22 Serum Creatinine: mg/dL > 2.5 3 > 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 valganciclovir tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant.

The majority of the adverse events were of mild or moderate intensity.

Table 5 Percentage of Selected Grades 1 to 4 Adverse Events Reported in greater than or equal to 5% of Adult Patients from a Study of Solid Organ Transplant Patients Adverse Event Valganciclovir Tablets (N=244) % Oral Ganciclovir (N=126) % Diarrhea 30 29 Tremors 28 25 Graft rejection 24 30 Nausea 23 23 Headache 22 27 Insomnia 20 16 Hypertension 18 15 Vomiting 16 14 Pyrexia 13 14 Table 6 shows selected adverse events regardless of severity and drug relationship with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either valganciclovir once daily starting within 10 days post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily starting within 10 days post-transplant until Day 200 post-transplant.

The overall safety profile of valganciclovir tablets 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 Events Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients Adverse Event Valganciclovir Tablets Day 100 Post-transplant (N=164) % Valganciclovir Tablets Day 200 Post-transplant (N=156) % Diarrhea 26 31 Tremors 12 17 Hypertension 13 12 Nausea 11 11 Pyrexia 12 9 Transplant rejection 9 6 Headache 10 6 Insomnia 7 6 Vomiting 3 6 Adverse events not included in Table 5 and Table 6 , which either occurred at a frequency of greater than or equal to 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients with a frequency of less than 5% are listed below.

Allergic reactions: valganciclovir hypersensitivity Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia, febrile neutropenia Hepatobiliary disorders: abnormal hepatic function Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection Injury, poisoning, and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne Vascular disorders : hypotension Laboratory abnormalities reported with valganciclovir tablets in two studies in adult solid organ transplant patients are listed in Table 7 and Table 8.

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 8 – <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< 500 500 – < 750 750 – <1000 9 6 7 10 6 5 Anemia: Hemoglobin g/dL< 6.5 6.5 – < 8 8 – <9.5 05 17 1 1 15 Thrombocytopenia: Platelets/µL<25000 25000 – < 50000 50000 – < 100000 0 1 7 00 3 Serum Creatinine: mg/dL> 2.5 > 1.5 – 2.5 17 50 14 48 *Laboratory abnormalities are those reported by investigators.

Adverse Events in Pediatric Patients: Valganciclovir tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 100 days [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 )].

Prevention of CMV Disease in Pediatric Solid Organ Transplant Patients: The most frequently reported adverse events (greater than 10% of patients), regardless of seriousness and drug relationship in pediatric solid organ transplant patients taking valganciclovir tablets until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, hypertension, vomiting, anemia, neutropenia, constipation, nausea and transplant rejection.

In general, the safety profile was similar in pediatric patients compared to that observed in adult patients.

However, the rates of certain adverse events and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 )].

Neutropenia was reported with higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC' s VALCYTE (valganciclovir hydrochloride) tablets.

However, due to Roche Palo Alto LLC' s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience The following adverse events have been identified during post-approval use of valganciclovir tablets.

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 tablets are rapidly and extensively converted to ganciclovir, any adverse events associated with ganciclovir might also occur with valganciclovir.– Anaphylaxis – Decreased fertility in males In general, the adverse events reported during the postmarketing use of valganciclovir tablets were similar to those identified during the clinical trials.

In general, the adverse events reported during the postmarketing use of valganciclovir tablets were similar to those identiƒed 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.