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valganciclovir 450 mg tablet generic valcyte

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Uses

Cytomegalovirus Retinitis

Valganciclovir hydrochloride tablets are used for initial (induction) treatment and maintenance treatment (secondary prophylaxis) of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS). The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) also recommend use of oral valganciclovir for treatment and secondary prophylaxis of CMV retinitis in HIV-infected older children and adolescents who can receive adult dosage. Safety and efficacy of oral valganciclovir have not been established for the treatment of congenital CMV disease.

The antiviral regimen used for initial treatment of CMV retinitis in HIV-infected patients should be selected based on the location and severity of CMV lesions, severity of underlying immunosuppression, concomitant drug therapy, and the patient's ability to adhere to the treatment regimen. Certain HIV specialists recommend use of oral valganciclovir in conjunction with an intraocular implant containing ganciclovir as the preferred regimen for initial treatment of CMV retinitis in HIV-infected adults or adolescents with immediate sight-threatening lesions (e.g., adjacent to the optic nerve or fovea), but state that oral valganciclovir may be adequate alone for the treatment of small peripheral lesions. CMV retinitis should be managed in consultation with an experienced ophthalmologist, and specialized references should be consulted for more specific information regarding initial treatment of CMV retinitis in HIV-infected individuals.

Because CMV disease is not cured with currently available antivirals, long-term suppressive or maintenance therapy (secondary prophylaxis) is recommended to prevent relapse in HIV-infected patients who have received initial treatment. The CDC, NIH, and IDSA state that the antiviral regimen used for secondary prophylaxis of CMV disease in HIV-infected individuals should be selected in consultation with a specialist. Although efficacy of valganciclovir as maintenance therapy has not been evaluated in comparative studies, use of the drug for this indication is supported by pharmacokinetic data in adults (i.e., the area under the concentration-time curve [AUC] for ganciclovir following oral administration of valganciclovir 900 mg daily is similar to that following IV administration of ganciclovir 5 mg/kg daily [the recommended IV dosage of ganciclovir for maintenance therapy of CMV retinitis in adults]).

Consideration can be given to discontinuing secondary prophylaxis against CMV in HIV-infected adults and adolescents with healed CMV retinitis who have had a sustained (e.g., 3-6 months) increase in CD4 T-cell counts to greater than 100/mm in response to antiretroviral therapy. The decision to discontinue such prophylaxis should be made in consultation with an ophthalmologist and in consideration of patient-specific factors (e.g., magnitude and duration of increase in CD4 T-cell count, anatomic location of retinal lesions, vision in the contralateral eye, feasibility of regular ophthalmologic monitoring). If secondary CMV prophylaxis is discontinued, the patient should continue to receive regular ophthalmologic monitoring (optimally every 3 months) to ensure early detection of CMV relapse or immune recovery uveitis. If CD4 T-cell counts decrease to less than 100/mm, secondary prophylaxis against CMV should be reinitiated.

Clinical Experience

In a randomized, open-label, comparative study (study WV15376) in HIV-infected adults (median age 39 years, baseline serum HIV-1 RNA levels of 4.9 log10, median CD4 T-cell count of 23/ mm, 91% male, 53% white, 31% Hispanic, 11% black) with previously untreated CMV retinitis, oral valganciclovir (900 mg twice daily for 21 days followed by 900 mg once daily for 7 days) was as effective as IV ganciclovir (5 mg/kg twice daily for 21 days followed by 5 mg/kg once daily for 7 days) in inhibiting CMV retinitis progression based on a masked evaluation of retinal photographs at week 4 of the study (the primary outcome measure).

All patients enrolled in study WV15376 received open-label valganciclovir after week 4; the median time to photographically determined first CMV retinitis progression in patients receiving induction therapy with oral valganciclovir or IV ganciclovir was 180 (mean: 226) or 126 (mean: 219) days, respectively.

Prevention of Cytomegalovirus Disease in Transplant Recipients

Valganciclovir hydrochloride tablets are used for prevention of CMV disease in adult kidney, heart, and kidney-pancreas transplant recipients considered at high risk for the disease (CMV-seronegative recipient of an organ from a CMV-seropositive donor).

Valganciclovir hydrochloride tablets or oral solution is used for prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age considered at high risk for the disease (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Safety and efficacy have not been established for prevention of CMV disease in any other pediatric solid organ transplant recipients.

Based on poor clinical study results in adults (see Clinical Experience under Uses: Prevention of Cytomegalovirus Disease in Transplant Recipients), valganciclovir should not be used for prevention of CMV disease in adult or pediatric liver transplant recipients. In addition, safety and efficacy of the drug for prevention of CMV disease in other solid organ transplant recipients (e.g., lung transplant recipients) have not been established.

Clinical Experience

Safety and efficacy of valganciclovir for prevention of CMV disease in solid organ transplant recipients were evaluated in a double-blind, double-dummy, active comparator study (study PV16000) in heart, liver, kidney, and kidney-pancreas transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Patients were randomized to receive oral valganciclovir (900 mg once daily) or oral ganciclovir (1 g 3 times daily) initiated within 10 days of transplantation and continued until 100 days after transplantation. During the first 6 months following transplantation, 12% of those receiving valganciclovir and 15% of those receiving ganciclovir developed CMV disease (CMV syndrome and/or tissue-invasive disease). However, in liver transplant recipients, the incidence of CMV disease was greater in those receiving valganciclovir (19%) than in those receiving ganciclovir (12%); tissue-invasive CMV disease was reported most frequently.

Safety and efficacy of a longer duration (200 days) of valganciclovir prophylaxis against CMV disease were established in a double-blind, placebo-controlled trial in adult kidney transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor). Patients were randomized to receive valganciclovir prophylaxis (900 mg once daily) starting within 10 days of transplantation and continued for 200 days posttransplantation or for 100 days posttransplantation followed by placebo for 100 days. At 1 year posttransplantation, the incidence of CMV disease was about 17% in those who received 200 days of valganciclovir prophylaxis compared with 37% in those who received only 100 days of such prophylaxis. There was no overall difference in the safety profile between the 2 groups.

Safety and pharmacokinetics of oral valganciclovir in pediatric patients were established in an open-label study of 63 solid organ transplant (i.e., kidney, liver, heart, kidney and liver) recipients 4 months to 16 years of age. These pediatric patients received once-daily valganciclovir (tablets or oral solution) given in a dose calculated based on body surface area (BSA) and estimated creatinine clearance (modified Schwartz formula) and limited to a maximum dosage of 900 mg daily. Valganciclovir treatment was initiated within 2 days posttransplantation and was continued for a maximum of 100 days (median duration was approximately 92 days). Pharmacokinetics of valganciclovir in these pediatric solid organ transplant patients were comparable to that reported in adult solid organ transplant patients receiving the drug at a dosage of 900 mg once daily. Although CMV viremia was reported in 11% of patients in this study, CMV disease was not reported in any pediatric patient up to 26 weeks posttransplantation. Use of valganciclovir for the prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk for the disease is based on pharmacokinetic, safety, and efficacy data from this open-label study and efficacy extrapolated from a study in adults. Safety and efficacy have not been established for prevention of CMV disease in any other pediatric solid organ transplant recipients.

Dosage and Administration

Administration

Valganciclovir hydrochloride is administered orally as tablets or an oral solution and should be given with food.

Valganciclovir oral solution is the preferred dosage form for pediatric patients. Valganciclovir tablets should be used in pediatric patients only if the calculated dose is within 10% of the tablet strength (i.e., a single 450-mg tablet may be used if the calculated dose is 405-495 mg).(See Pediatric Dosage under Dosage and Administration: Dosage.)

Adults should receive valganciclovir tablets (not the oral solution).

Oral Solution

Valganciclovir hydrochloride powder for oral solution should be reconstituted at the time of dispensing by adding 91 mL of purified water to provide a solution containing 250 mg of valganciclovir per 5 mL. After tapping the bottle to loosen the powder, the water should be added in 2 approximately equal portions and the bottle should be shaken for 1 minute after each addition. Following reconstitution, the solution is colorless to brownish yellow.

The reconstituted oral solution should be stored at 2-8°C for up to 49 days and should not be frozen.

Just prior to each dose, the oral solution should be shaken for about 5 seconds. The solution should be administered using the bottle adapter and dosing dispenser provided by the manufacturer.

Dosage

Dosage of valganciclovir hydrochloride is expressed in terms of valganciclovir.

Valganciclovir hydrochloride tablets and ganciclovir capsules are not bioequivalent in terms of ganciclovir bioavailability; valganciclovir hydrochloride tablets cannot be substituted for ganciclovir capsules on a one-to-one basis.

Adult Dosage

Cytomegalovirus Retinitis

For initial (induction) treatment of cytomegalovirus (CMV) retinitis in adults with normal renal function (creatinine clearance 60 mL/minute or greater), the recommended dosage of valganciclovir tablets is 900 mg twice daily for 21 days. The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) recommend a duration of 14-21 days for initial (induction) treatment.

After completion of induction therapy or in patients with inactive CMV retinitis, the recommended dosage of valganciclovir tablets for long-term suppressive or maintenance therapy (secondary prophylaxis) in adults with normal renal function is 900 mg once daily.

Prevention of Cytomegalovirus Disease in Transplant Recipients

For prevention of CMV disease in adults at high risk undergoing heart or kidney-pancreas transplantation, the usual dosage of valganciclovir tablets is 900 mg once daily initiated within 10 days of transplantation and continued until 100 days posttransplantation.

For prevention of CMV disease in adults at high risk undergoing kidney transplantation, the usual dosage of valganciclovir tablets is 900 mg once daily initiated within 10 days of transplantation and continued until 200 days posttransplantation.

Pediatric Dosage

CMV Retinitis

If oral valganciclovir is used for initial (induction) therapy in older children and adolescents who can receive adult dosage, the CDC, NIH, and IDSA recommend 900 mg twice daily for 14-21 days.

If oral valganciclovir is used for maintenance therapy (secondary prophylaxis) of CMV retinitis in older children and adolescents who can receive adult dosage, the CDC, NIH, and IDSA recommend 900 mg once daily.

Prevention of Cytomegalovirus Disease in Transplant Recipients

For prevention of CMV disease in children 4 months to 16 years of age at high risk undergoing heart or kidney transplantation, valganciclovir should be given once daily initiated within 10 days of transplantation and continued until 100 days posttransplantation. The pediatric dose should be individualized based on body surface area (BSA) and estimated creatinine clearance (Clcr, modified Schwartz formula), and is calculated using the following pediatric dosage equation:

Pediatric dose (in mg) = 7 x BSA (in m2) x Clcr (modified Schwartz formula)Modified Schwartz Clcr (in mL/minute per 1.73 m2) = [k x height (in cm)]/ serum creatinine (in mg/dL)Where k = 0.45 for patients 4 months to <2 years of age, 0.55 for girls 2-16 years of age, 0.55 for boys 2 to <13 years of age, and 0.7 for boys 13-16 years of age.

To prevent overdosage, the estimated creatinine clearance used to calculate the pediatric dose should not exceed 150 mL/min per 1.73 m, regardless of the value calculated using the modified Schwartz formula. If the estimated creatinine clearance exceeds 150 mL/min per 1.73 m, the value of 150 mL/min per 1.73 m should be used to calculate the dose for that patient. The calculated dose should be rounded to the nearest 25-mg increment. The maximum dose is 900 mg.

Special Populations

In patients with impaired renal function, dosage and/or frequency of administration of valganciclovir must be modified in response to the degree of impairment.

Dosage for pediatric patients with renal impairment can be calculated using the usually recommended pediatric dosage equation since this is based on both BSA and estimated creatinine clearance.(See Pediatric Dosage under Dosage and Administration: Dosage.)

Dosage for adults with renal impairment should be based on the patient's creatinine clearance, which can be estimated using the following formula:

Ccr male = [(140 - age in years) x weight (in kg)] / [72 x serum creatinine (in mg/dL)]Ccr female = 0.85 x Ccr male

Cytomegalovirus Retinitis

For initial (induction) treatment of CMV retinitis in adults with renal impairment, the manufacturer recommends that adults with creatinine clearances of 40-59 mL/minute receive valganciclovir 450 mg twice daily, those with creatinine clearances of 25-39 mL/minute receive 450 mg once daily, and those with creatinine clearances of 10-24 mL/minute receive 450 mg every 2 days.

For maintenance therapy (secondary prophylaxis) following completion of induction therapy or in patients with inactive CMV retinitis, the manufacturer recommends a valganciclovir dosage of 450 mg once daily for adults with creatinine clearances of 40-59 mL/minute, 450 mg every 2 days for those with creatinine clearances of 25-39 mL/minute, and 450 mg twice weekly for those with creatinine clearances of 10-24 mL/minute.

Valganciclovir should not be used in adults undergoing hemodialysis (creatinine clearance less than 10 mL/minute); such patients should receive ganciclovir (with appropriate dosage modification) rather than valganciclovir.(See Specific Populations: Renal Impairment, under Warnings/Precautions, in Cautions.)

Cautions

Contraindications

Known hypersensitivity to valganciclovir, ganciclovir, or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hematologic Effects

Toxicity of valganciclovir, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia.

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients receiving valganciclovir or ganciclovir. Cytopenia may occur at any time and the degree of cytopenia may increase with continued valganciclovir therapy. Cell counts usually begin to return to baseline 3-7 days after discontinuance of the drug.

Complete blood cell counts (CBCs) and platelet counts should be performed frequently, especially in those with baseline neutrophil counts less than 1000/mm and in those who have experienced leukopenia while receiving ganciclovir or other nucleoside analogs. More frequent monitoring for cytopenias may be warranted if therapy is changed from oral ganciclovir to valganciclovir (because of comparatively increased plasma ganciclovir concentrations with valganciclovir).

Valganciclovir should not be used in patients with an absolute neutrophil count less than 500/mm, a platelet count less than 25,000/mm, or a hemoglobin concentration less than 8 g/dL. Use with caution in patients with preexisting cytopenias and in those who have received or are receiving concomitant myelosuppressive drugs or irradiation.

Carcinogenesis, Mutagenesis, Teratogenesis, Impairment of Fertility

Animal data indicate that ganciclovir is carcinogenic, mutagenic, teratogenic, and causes aspermatogenesis. Valganciclovir is converted to ganciclovir and is expected to have carcinogenic and reproductive toxic effects similar to those of ganciclovir. Valganciclovir can be considered a potential carcinogen in humans and may be teratogenic or embryotoxic at usual therapeutic doses. It is considered likely that valganciclovir will produce temporary or permanent inhibition of spermatogenesis and also may suppress fertility in females.

Women of childbearing potential should be advised to use an effective method of contraception during and for at least 30 days after valganciclovir therapy.

Men should be advised to use a reliable method of barrier contraception during and for at least 90 days after valganciclovir therapy.

Other Warnings/Precautions

Renal Effects

Acute renal failure may occur in geriatric patients (with or without renal impairment), patients receiving potentially nephrotoxic drugs, and inadequately hydrated patients.

Adequate hydration should be maintained in all patients.

Use caution and adjust valganciclovir dosage based on creatinine clearance.(See Dosage and Administration: Special Populations.)

Use caution in patients receiving concomitant therapy with potentially nephrotoxic drugs.

Adherence to Dosage Regimen

Adherence to dosage recommendations is essential to avoid overdosage. In pediatric patients, adhere to the recommended pediatric dosage equation, maximum estimated creatinine clearance, and maximum daily dosage. (See Pediatric Dosage under Dosage and Administration: Dosage.)

Bioavailability of ganciclovir from valganciclovir tablets is substantially higher than from ganciclovir capsules, and the tablets and capsules cannot be substituted on a one-to-one basis.

Handling and Disposal

Because valganciclovir is considered a potential teratogen and carcinogen, observe caution when handling the drug. Valganciclovir tablets should not be broken or crushed. Avoid direct contact of broken or crushed tablets, powder for oral solution, or reconstituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with water. For further information on handling of cytotoxic drugs, see the guidelines at the end of Antineoplastic Agents 10:00.

Specific Populations

Pregnancy

Category C.

Valganciclovir is expected to have reproductive toxicity similar to ganciclovir.(See Carcinogenesis, Mutagenesis, Teratogenesis, Impairment of Fertility under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Not known whether valganciclovir or ganciclovir is distributed into human milk.

Because of the potential for serious adverse reactions to ganciclovir in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. HIV-infected mothers should be instructed not to breast-feed their infants because of the risk of transmission of HIV.

Pediatric Use

Safety and efficacy of valganciclovir have not been established in pediatric patients younger than 4 months of age.

Use of valganciclovir for the prevention of cytomegalovirus (CMV) disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk is based on pharmacokinetic, safety, and efficacy data from an open-label study in this age group and efficacy extrapolated from a study in adults. Safety and efficacy have not been established for prevention of CMV disease in any other pediatric solid organ transplant recipients.

Safety and efficacy have not been established for the treatment of congenital CMV disease.

Geriatric Use

Experience in those 65 years of age or older insufficient to determine whether they respond differently from younger adults. Pharmacokinetics not studied in geriatric patients. Because geriatric individuals frequently have decreased renal function (e.g., glomerular filtration), particular attention should be paid to assessing renal function before and during therapy. If evidence of renal impairment exists or develops, appropriate dosage adjustments should be made. Drug dosage should be selected carefully, taking into account the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Renal Impairment

The major route of elimination of valganciclovir is renal excretion as ganciclovir; therefore, clearance of the drug depends on renal function. If renal function is impaired, the dosage of valganciclovir must be adjusted based on measured or estimated creatinine clearance. (See Dosage and Administration: Special Populations.)

Hemodialysis reduces plasma concentrations of ganciclovir by about 50%. Valganciclovir should not be used in adults undergoing hemodialysis because the appropriate daily dose for such patients is lower than 450 mg (i.e., would require breaking a tablet); such patients should receive ganciclovir instead.

Hepatic Impairment

Safety and efficacy of valganciclovir have not been evaluated in patients with hepatic impairment.

Common Adverse Effects

Adverse effects occurring in 5% or more of adults receiving valganciclovir include abdominal pain, anemia, diarrhea, graft rejection, increased serum creatinine, headache, insomnia, leukopenia, nausea, neutropenia, paresthesia, peripheral neuropathy, pyrexia, retinal detachment, thrombocytopenia, tremors, and vomiting.

Adverse effects occurring in 10% or more of pediatric patients receiving valganciclovir include diarrhea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation, nausea, and cough. Adverse effects reported more frequently in pediatric patients than in adults include upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and neutropenia.

Drug Interactions

No formal drug interaction studies have been performed using valganciclovir. However, valganciclovir is rapidly and extensively converted to ganciclovir and interactions associated with ganciclovir are expected to occur in patients receiving valganciclovir.

Didanosine

Potential pharmacokinetic interaction (increased plasma concentrations of didanosine); monitor for didanosine toxicity.

Mycophenolate Mofetil

Potential pharmacokinetic interaction in patients with renal impairment (increased plasma concentrations of the metabolites of both drugs).

Myelosuppressive Agents or Irradiation

Potential pharmacologic interactions (additive hematologic toxicity).

Probenecid

Potential pharmacokinetic interaction (decreased renal clearance and increased AUC of ganciclovir); monitor for ganciclovir toxicity.

Zidovudine

Potential pharmacologic interaction (additive hematologic toxicity [neutropenia, anemia]).

Pharmacokinetics

Absorption

Bioavailability

Valganciclovir, a prodrug of ganciclovir, is well absorbed from GI tract and metabolized by intestinal and hepatic esterases to ganciclovir. Systemic exposure to prodrug is transient and low.

GI absorption of valganciclovir substantially greater than absorption of oral ganciclovir resulting in plasma ganciclovir concentrations comparable to those achieved with IV ganciclovir.

Absolute bioavailability of ganciclovir approximately 60% when oral valganciclovir given with food. Time to peak ganciclovir concentrations 1-3 hours.

Food

Administration of valganciclovir with a high-fat meal (approximately 600 calories, 31 g fat) increases area under the concentration-time curve (AUC) and peak plasma concentrations of ganciclovir at steady-state by 30 and 14%, respectively.

Distribution

Extent

Ganciclovir crosses the placenta (based on an ex vivo human placental model). Not known whether ganciclovir or valganciclovir distributed into human milk.

Plasma Protein Binding

Ganciclovir plasma protein binding 1-2%; protein binding of valganciclovir not determined because of rapid conversion to ganciclovir.

Elimination

Metabolism

Valganciclovir rapidly hydrolyzed to ganciclovir; no other metabolites detected. Ganciclovir phosphorylated to ganciclovir phosphate in cytomegalovirus (CMV)-infected cells.

Elimination Route

Major route of elimination of valganciclovir is renal excretion as ganciclovir by glomerular filtration and active tubular secretion.

Half-life

The mean half-life of ganciclovir after oral administration of valganciclovir is approximately 4 hours in healthy or HIV-positive/CMV-positive adults (with or without retinitis) and 6.6-6.8 hours in adult heart, kidney, and kidney-pancreas transplant recipients.

The half-life of ganciclovir after oral administration of valganciclovir is 2.8-4.8 hours in pediatric solid organ transplant recipients 4 months through 11 years of age and 4.4-6 hours in pediatric solid organ transplant recipients 12 years of age or older. Clearance is influenced by body surface area (BSA) and renal function.

Special Populations

Pharmacokinetics not evaluated in hepatic impairment.

The half-life of ganciclovir after oral administration of valganciclovir is increased in renal impairment. Data from otherwise healthy adults with renal impairment indicate the mean half-life is about 22 hours if creatinine clearance is 11-20 mL/minute and about 68 hours if creatinine clearance is 10 mL/minute or less.

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