Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3758
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Valcyte (Tablet, Film Coated)
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Strict adherence to dosage recommendations is essential to avoid overdose. Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis. Valcyte tablets are administered orally, and should be taken with food . After oral administration, valganciclovir is rapidly and extensively converted into ganciclovir. The bioavailability of ganciclovir from Valcyte tablets is significantly higher than from ganciclovir capsules. Therefore the dosage and administration of Valcyte tablets as described below should be closely followed .<br/>For the Treatment of CMV Retinitis in Patients With Normal Renal Function:<br/>Induction: For patients with active CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) twice a day for 21 days with food.<br/>Maintenance: Following induction treatment, or in patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) once daily with food.<br/>For the Prevention of CMV Disease in Heart, Kidney, and Kidney-Pancreas Transplantation: For patients who have received a kidney, heart, or kidney-pancreas transplant, the recommended dose is 900 mg (two 450 mg tablets) once daily with food starting within 10 days of transplantation until 100 days posttransplantation.<br/>Renal Impairment: Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required according to creatinine clearance as shown in Table 13 . Increased monitoring for cytopenias may be warranted in patients with renal impairment .<br/>Hemodialysis Patients: Valcyte should not be prescribed to patients receiving hemodialysis . For patients on hemodialysis (CrCl<10 mL/min) a dose recommendation cannot be given .<br/>Handling and Disposal: Caution should be exercised in the handling of Valcyte tablets. Tablets should not be broken or crushed. Since valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets . Avoid direct contact of 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. Because ganciclovir shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published . There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
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Valcyte (valganciclovir HCl tablets) contains valganciclovir hydrochloride (valganciclovir HCl), 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 cytomegalovirus (CMV). Valcyte is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. The film-coat applied to the tablets contains Opadry Pink. Valganciclovir HCl is a white to off-white crystalline powder with a molecular formula of CHNO���HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25��C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir HCl is 7.6. The chemical structure of valganciclovir HCl is: All doses in this insert are specified in terms of valganciclovir.
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Pharmacokinetics: BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR VALCYTE TABLETS. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION. The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients. The ganciclovir pharmacokinetic measures following administration of 900 mg Valcyte and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 1. The area under the plasma concentration-time curve (AUC) for ganciclovir administered as Valcyte tablets is comparable to the ganciclovir AUC for intravenous ganciclovir. Ganciclovir Cfollowing Valcyte administration is 40% lower than following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUCand Cfollowing oral ganciclovir administration (1000 mg three times daily) are lower relative to Valcyte and intravenous ganciclovir. The ganciclovir Cfollowing intravenous ganciclovir and Valcyte administration are less than the ganciclovir Cfollowing oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics for these three ganciclovir delivery systems is unknown. Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients* *Plasma concentration-time profiles for ganciclovir (GCV) from Valcyte (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (WV15376 n=21 and n=18, respectively) in HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (GAN2230 n=24) in HIV-positive/CMV-positive patients withoutCMV retinitis. In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7��higher following administration of 900 mg Valcyte tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation (seeTable 2). In a pharmacokinetic study in liver transplant patients, the ganciclovir AUCachieved with 900 mg valganciclovir was 41.7��9.9��g���h/mL (n=28) and the AUCachieved with the approved dosage of 5 mg/kg intravenous ganciclovir was 48.2��17.3��g���h/mL (n=27).<br/>Absorption: Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from Valcyte tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median Tfollowing administration of 450 mg to 2625 mg Valcyte tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of Valcyte tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUCand Cvalues are approximately 1% and 3% of those of ganciclovir, respectively.<br/>Food Effects: When Valcyte tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the Cincreased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (T). Valcyte tablets should be administered with food .<br/>Distribution: Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51��g/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703��0.134 L/kg (n=69). After administration of Valcyte tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Valcyte tablets according to weight is not required.<br/>Metabolism: Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.<br/>Elimination: The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07��0.64 mL/min/kg (n=68) while renal clearance was 2.99��0.67 mL/min/kg (n=16). The terminal half-life (t) of ganciclovir following oral administration of Valcyte tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08��0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81��0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of Valcyte was 6.48��1.38 hours, and following oral administration of ganciclovir capsules was 8.56��3.62.<br/>Special Populations:
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Valcyte tablets are contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir.
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Valcyte (valganciclovir HCl tablets) is available as 450 mg pink convex oval tablets with "VGC" on one side and "450" on the other side. Each tablet contains valganciclovir HCl equivalent to 450 mg valganciclovir. Valcyte is supplied in bottles of 60 tablets (NDC 0004-0038-22).<br/>Storage: Store at 25��C (77��F); excursions permitted to 15��C to 30��C (59��F to 86��F) [See USP controlled room temperature].
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WARNING: THE CLINICAL TOXICITY OF VALCYTE, WHICH IS METABOLIZED TO GANCICLOVIR, INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.
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General: Strict adherence to dosage recommendations is essential to avoid overdose. The bioavailability of ganciclovir from Valcyte tablets is significantly higher than from ganciclovir capsules. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of Valcyte tablets. Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis . Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED FOR VALCYTE TABLETS. Such adjustments should be based on measured or estimated creatinine clearance values . For patients on hemodialysis (CrCl<10 mL/min) it is recommended that ganciclovir be used (in accordance with the dose-reduction algorithm cited in the Cytovene-IV and ganciclovir capsules complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment) rather than Valcyte tablets .<br/>Information for Patients: (see Patient Information) Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of Valcyte tablets . Valcyte is changed to ganciclovir once it is absorbed into the body. All patients should be informed that the major toxicities of ganciclovir include granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Patients should be informed that ganciclovir has beenassociated with elevations in serum creatinine. Patients should be instructed to take Valcyte tablets with food to maximize bioavailability. Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause decreased fertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy. Because of the potential for serious adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving Valcyte tablets. Women of childbearing potential should be advised to use effective contraception during treatment with Valcyte tablets. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Valcyte tablets. Although there is no information from human studies, patients should be advised that ganciclovir should be considered a potential carcinogen. Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of Valcyte tablets and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness including the patient's ability to drive and operate machinery. Patients should be told that ganciclovir is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment. Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with Valcyte tablets. Some patients will require more frequent follow-up.<br/>Laboratory Testing: Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Valcyte tablets , it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/��L at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to Valcyte, because of increased plasma concentrations of ganciclovir after Valcyte administration . Increased serum creatinine levels have been observed in trials evaluating Valcyte tablets. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients . The mechanism of impairment of renal function is not known.<br/>Drug Interactions:<br/>Drug Interaction Studies Conducted With Valcyte: No in vivo drug-drug interaction studies were conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for Valcyte tablets.<br/>Drug Interaction Studies Conducted With Ganciclovir: Binding of ganciclovir to plasma proteins is only about 1% to 2%, and drug interactions involving binding site displacement are not anticipated. Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Valcyte tablets and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: No long-term carcinogenicity studies have been conducted with Valcyte. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen. Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1��and 1.4��, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductivetissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans. Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay. Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir . Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7��the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1��the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir (and valganciclovir) could cause inhibition of human spermatogenesis.<br/>Pregnancy:<br/>Category C: Valganciclovir is converted to ganciclovir and therefore is expected to have reproductive toxicity effects similar to ganciclovir. Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered doses that produced 2��the human exposure based on AUC comparisons. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach . The drug exposure in mice as estimated by the AUC was approximately 1.7��the human AUC. Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion. Valganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. Valcyte tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: It is not known whether ganciclovir or valganciclovir is excreted in human milk. Because valganciclovir caused granulocytopenia, anemia and thrombocytopenia in clinical trials and ganciclovir was mutagenic and carcinogenic in animal studies, the possibility of serious adverse events from ganciclovir in nursing infants is possible . Because of potential for serious adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving Valcyte tablets. In addition, the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants toavoid risking postnatal transmission of HIV.<br/>Pediatric Use: Safety and effectiveness of Valcyte tablets in pediatric patients have not been established.<br/>Geriatric Use: The pharmacokinetic characteristics of Valcyte in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of Valcyte . Clinical studies of Valcyte did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Valcyte is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly .
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valganciclovir hydrochloride
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Valcyte (Tablet, Film Coated)
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Valcyte tablets are indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) . Valcyte is indicated for the prevention of cytomegalovirus (CMV) disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [(D+/R-)]). Valcyte is not indicated for use in liver transplant patients . The safety and efficacy of Valcyte for the prevention of CMV disease in other solid organ transplant patients such as lung transplant patients have not been established.
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Valcyte
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