VALGANCICLOVIR

Valganciclovir tablets, USP contains valganciclovir hydrochloride, USP 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 tablets, USP are available as a 450 mg tablet for oral administration. Each film coated tablet contains 496.3 mg of valganciclovir hydrochloride, USP (corresponding to 450 mg of valganciclovir), and the inactive ingredients crospovidone, microcrystalline cellulose, povidone and stearic acid. The tablets are coated with Opadry Pink which contains hypromellose, iron oxide red, polyethylene glycol, polysorbate 80 and titanium dioxide. Valganciclovir hydrochloride, USP is a white to off-white powder, slightly hygroscopic 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, USP is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropylester, monohydrochloride. Valganciclovir hydrochloride, USP is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7 and an n-octanol/water partition coefficient of 0.0095 at pH 7. The pKa for valganciclovir hydrochloride, USP is 7.5. The chemical structure of valganciclovir hydrochloride, USP is: All doses in this insert are specified in terms of valganciclovir. valganciclovirstructure

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.

DOSAGE & ADMINISTRATION 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 heart transplant patients 4 months 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 tablets should be taken with food ( 2.1 , 12.3 ). • Valganciclovir tablets should not be broken or crushed ( 2.6 ). • Adult patients should use valganciclovir tablets, not valganciclovir 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 tablets, not valganciclovir for oral solution. • Valganciclovir 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 Heart Transplant Patients : For pediatric heart transplant patients 4 month to 16 years of age, the recommended once daily mg dose (7x BSA x CrCL) should start within 10 days of transplantation until 100 days post-transplantation. The recommended once daily dosage of valganciclovir 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. Mosteller BSA (m 2 ) = √ Height (cm) x weight (kg) 3600 Schwartz Creatinine Clearance (mL/min/1.73m 2 ) = K x Height (cm) Serum Creatinine (mg/dL) 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 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. 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. 2.5 Dosage Recommendation for Adult Patients with Renal Impairment Serum creatinine levels or creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), a dose recommendation for 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 ≥ 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 *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 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 ( 5.3, 5.4 )]. 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 .

Valganciclovir tablets are 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 )

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.

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 valganciclovir tablets. 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 Zidovudine ↓ Ganciclovir ↑ Zidovudine Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia Probenicid ↑ Ganciclovir Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase Didanosine ↓ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity • Zidovudine: Potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels (7 ). • Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity (7 ). • Mycophenolate mofetil (MMF): May increase ganciclovir concentrations and levels of MMF metabolites in patients with renal impairment. Monitor for ganciclovir and MMF toxicity ( 7 ). • Didanosine: May increase didanosine concentrations. Monitor for didanosine toxicity ( 7 ).