Valganciclovir Drug Information

Pediatric Patients Prevention of

CMV Disease: Valganciclovir 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 .

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 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 Nausea 30 Vomiting 21 Abdominal pain 15 General disorders and administrative site conditions Pyrexia 31 Nervous system disorders Headache 22 Insomnia 16 Neuropathy peripheral 9 Paresthesia 8 Eye disorders Retinal detachment 15 Table 4 Pooled Selected Laboratory Abnormalities Reported in Patients Who Received Valganciclovir Tablets Maintenance Therapy for the Treatment of CMV Retinitis Patients with CMV Retinitis Laboratory Abnormalities Valganciclovir Tablets (N=370) % Neutropenia: ANC/µL < 500 19 500 to < 750 17 750 to < 1000 17 Anemia: Hemoglobin g/dL < 6.5 7 6.5 to < 8.0 13 8.0 to < 9.5 16 Thrombocytopenia: Platelets/µL < 25000 4 25000 to < 50000 6 50000 to < 100000 22 Serum Creatinine: mg/dL > 2.5 3 > 1.5 to 2.5 12 Prevention of CMV Disease in Solid Organ Transplant Patients: Table 5 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received valganciclovir tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse reactions were of mild or moderate intensity. Table 5 Percentage of Selected Grades 1-4 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 for oral solution 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 3 500 to < 750 3 2 750 to < 1000 5 2 Anemia: Hemoglobin g/dL < 6.5 1 2 6.5 to < 8.0 5 7 8.0 to < 9.5 31 25 Thrombocytopenia: Platelets/µL < 25000 0 2 25000 to < 50000 1 3 50000 to < 100000 18 21 Serum Creatinine: mg/dL > 2.5 14 21 > 1.5 to 2.5 45 47 *Laboratory abnormalities are those reported by investigators.

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

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.

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. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function.

Following concomitant administration of valganciclovir 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 Concomit a nt 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 valganciclovir is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine. 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 valganciclovir 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 Valganciclovir 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. Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function.

Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. 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.

Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity.

Pediatric Use Valganciclovir for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age and in pediatric heart transplant patients 1 month to 16 years of age at risk for developing CMV disease. The use of valganciclovir hydrochloride for oral solution and tablets for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients 4 months to 16 years of age. Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). Valganciclovir was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation.

Study 2 was a safety and tolerability study where valganciclovir was administered once daily within 10 days of transplantation for a maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients. The use of valganciclovir for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 1 month to 16 years of age is based on two studies (Study 1 described above and Study 3) and was supported by previous demonstration of efficacy in adult patients . Study 3 was a pharmacokinetic and safety study of valganciclovir for oral solution in pediatric heart transplant patients less than 4 months of age who received a single dose of valganciclovir for oral solution on each of two consecutive days.

A physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than 1 month of age. However, due to uncertainty in model predictions for neonates, valganciclovir for oral solution is not indicated for prophylaxis in this age group. The safety and efficacy of valganciclovir for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of valganciclovir for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or valganciclovir for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of valganciclovir for oral solution provided ganciclovir systemic exposures (median AUC 0-12h = 23.6 mcg ∙ h/mL; n = 6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC 0-12h = 25.3 mcg ∙ h/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of valganciclovir tablets twice daily.

However, the efficacy and safety of intravenous ganciclovir and of valganciclovir for oral solution have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.

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. Hypersensitivity to valganciclovir or ganciclovir.

• Experience with Valganciclovir Tablets: An overdose of valganciclovir could possibly result in increased renal toxicity . Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered . Reports of adverse reactions after overdoses with valganciclovir, some with fatal outcomes, have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events: Hematological toxicity: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopenia Hepatotoxicity: hepatitis, liver function disorder Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting Neurotoxicity: generalized tremor, seizure