Valcyte Drug Information

• Adult Patients Treatment of Cytomegalovirus (CMV) Retinitis: VALCYTE is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).
• Prevention of CMV Disease: VALCYTE 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 ).

Pediatric Patients Prevention of CMV Disease: VALCYTE 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.

General Dosing Information

Adult patients should use VALCYTE tablets, not VALCYTE for oral solution. VALCYTE for oral solution and tablets should be taken with food. VALCYTE for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient.

Recommended Dosage in Adult Patients with Normal Renal Function For dosage recommendations in adult patients with renal impairment. 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. 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 × BSA × CrCl) should start within 10 days of transplantation until 100 days post-transplantation. The recommended once daily dosage of VALCYTE 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 × BSA × CrCl (calculated using a modified Schwartz formula).

The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 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.

VALCYTE for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, VALCYTE 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 VALCYTE tablets, pediatric patients should be assessed for the ability to swallow tablets.

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Preparation of VALCYTE 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, VALCYTE for oral solution must be prepared by the pharmacist as follows: Measure 91 mL of purified water in a graduated cylinder. Shake the VALCYTE 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. 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.

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 VALCYTE cannot be given.

Handling and Disposal Caution should be exercised in the handling of VALCYTE tablets and VALCYTE 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.

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 VALCYTE according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity). 2

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 VALCYTE.

The incidence of adverse reactions was similar between the group who received VALCYTE tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/µL) were 11% for patients receiving VALCYTE 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 VALCYTE tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received VALCYTE 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 VALCYTE Tablets Maintenance Therapy for CMV Retinitis Reported in Patients Who Received VALCYTE Tablets Maintenance Therapy for the Treatment of CMV Retinitis 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 VALCYTE 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 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 VALCYTE did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients. Table 7 Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients Reported in a Study of Adult Kidney Transplant Patients Other adverse drug reactions from VALCYTE in clinical trials in CMV retinitis and solid organ transplant patients Other adverse drug reactions with VALCYTE 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 VALCYTE 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: VALCYTE 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 VALCYTE 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 VALCYTE was similar with the extension of prophylaxis until Day 200 post-transplant in high risk pediatric kidney transplant patients. There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated 100 or 200 days with VALCYTE.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VALCYTE. 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 VALCYTE 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 VALCYTE were similar to those identified during the clinical trials.

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 Monitor renal function when VALCYTE is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine.: 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.

Pregnancy Risk Summary After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, VALCYTE is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of VALCYTE or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and the risk of miscarriage is 15–20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is a result of maternal viremia and transplacental infection.

Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in these infants is about 10% and approximately 50–90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems.

The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection. Data Animal Data Doses resulting in two-times the human exposure of ganciclovir (based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryo-fetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice.

Rabbits showed increased embryo-fetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryo-fetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7 times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach.

Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL.

Pediatric Use VALCYTE 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 VALCYTE 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).

VALCYTE was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation. The results of these studies were supported by previous demonstration of efficacy in adult patients. The use of VALCYTE 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 VALCYTE in pediatric heart transplant patients less than 4 months of age who received a single dose of VALCYTE 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, VALCYTE is not indicated for prophylaxis in this age group.

The safety and efficacy of VALCYTE 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 VALCYTE 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 VALCYTE 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 VALCYTE 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 VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE 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.

VALCYTE 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 VALCYTE Tablets: An overdose of VALCYTE 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 VALCYTE. 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