Valcyte^{TM Pr}

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Pharmacology

Valganciclovir is an L-valyl ester salt (prodrug) of ganciclovir that exists as a mixture of 2 diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses in vitro and in vivo. 

In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. This has been shown to occur in CMV-infected cells (half-life 18 hours) and HSV-infected cells (half-life between 6 and 24 hours) after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

The median concentration of ganciclovir that inhibits CMV replication (IC₅₀) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.58 µg/mL (0.08 to 14.32 µM). Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in vitro at higher concentrations ranging from 10.21 to >250 µg/mL (40 to >1000 µM). Bone marrow-derived colony-forming cells are more sensitive (CIC₅₀ 0.69 to 3.06 µg/mL; 2.7 to 12 µM). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Pharmacokinetics: The pharmacokinetics of valganciclovir were predominantly performed in HIV/CMV-seropositive patients and HIV-positive patients with CMV retinitis. The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of i.v. administered ganciclovir was 3.05±0.81 mL/min/kg (n=86) while renal clearance was 2.40±0.93 mL/min/kg (n=46).

The terminal half-life (t_1/2) of ganciclovir following oral administration of valganciclovir tablets to either healthy or HIV-positive/CMV-positive subjects was 4.18±0.80 hours (n=244), and that following administration of i.v. ganciclovir was 3.85±0.74 hours (n=87).

Valganciclovir is well absorbed from the GI tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir tablets following food was approximately 60% (3 studies, n=18; n=16; n=28). Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir tablets in the dose range of 450 to 2625 mg was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, was transient and low, and the AUC₂₄ and C_max values were approximately 1% and 3% of those of ganciclovir, respectively.

When valganciclovir tablets were administered with food at a dose of 900 mg, the area under the plasma concentration time curve (AUC) over 24 hours was 28.0±8.9 µg•h/mL (n=75), and the maximum plasma concentration (C_max) was 5.37±1.53 µg/mL (n=76).

Food Effects: When valganciclovir tablets were administered with a meal containing 569 calories (31.1 g fat, 51.6 g carbohydrates, and 22.2 g protein) at a dosage 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 C_max increased by 14% (95% CI, 5 to 36%), without any prolongation in time to peak plasma concentrations (T_max). Therefore it is recommended that valganciclovir tablets be administered with food (see Dosage).

Clinical Studies: Induction Therapy of CMV Retinitis: Study WV15376: In a randomized, open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either valganciclovir tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with i.v. ganciclovir solution (5 mg/kg twice daily for 21 days, then 5 mg/kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log₁₀, and the median CD4 cell count was 23 cells/mm³. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and week 4 was the primary outcome measurement of the 3-week induction therapy. Table I provides the outcomes at 4 weeks.

Maintenance Therapy of CMV Retinitis: No comparative clinical data are available on the efficacy of valganciclovir for the maintenance therapy of CMV retinitis because all patients in study WV15376 received open-label valganciclovir after week 4. However, the AUC for ganciclovir is similar following administration of 900 mg valganciclovir once daily and 5 mg/kg i.v. ganciclovir once daily. Although the ganciclovir C_max is lower following valganciclovir administration compared to i.v. ganciclovir, it is higher than the C_max obtained following oral ganciclovir administration. Therefore, use of valganciclovir as maintenance therapy is supported by a plasma concentration-time profile similar to that of 2 approved products for maintenance therapy of CMV retinitis.

Indications

For the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.

Diagnosis of CMV Retinitis: The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason, it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions. The diagnosis of CMV retinitis may be supported by a positive culture of CMV from urine, blood, throat or other sites, but a negative culture of CMV does not rule out CMV retinitis.

Contraindications

In patients with known hypersensitivity to valganciclovir, ganciclovir or to any component of the product.

Due to the similarity of the chemical structure of valganciclovir and that of acyclovir and valacyclovir, a cross-hypersensitivity reaction between these drugs is possible.

Warnings

The clinical toxicity of valganciclovir tablets includes granulocytopenia, anemia and thrombocytopenia. In animal and in vitro studies ganciclovir was mutagenic, carcinogenic, teratogenic and caused aspermatogenesis. Therefore it should be considered a potential teratogen and carcinogen in humans. Valganciclovir is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks. Safety and efficacy of valganciclovir tablets have not been established for congential or neonatal CMV disease; nor for the treatment of established CMV disease other than retinitis; nor for use in nonimmunocompromised individuals.

Hematologic: Valganciclovir tablets should not be administered if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25 000/µL, or the hemoglobin is less than 80 g/L. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with valganciclovir tablets (and ganciclovir) (see Precautions, Laboratory Testing; Adverse Effects and Dosage, Patients with Severe Leukopenia, Neutropenia, Anemia, Thrombocytopenia and/or Pancytopenia).

Valganciclovir tablets should, therefore, be used with caution in patients with pre-existing cytopenias, or who have received or are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may increase with continued dosing. Cell counts usually begin to recover within 3 to 7 days of discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil counts in patients receiving ganciclovir for treatment of CMV retinitis.

Pregnancy and Reproduction: Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses (see Precautions, Carcinogenesis, Mutagenesis). It is considered probable that in humans, valganciclovir at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur.

Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment. Similarly, men should be advised to practice barrier contraception during, and for at least 90 days following, treatment with valganciclovir tablets (see Precautions, Carcinogenesis, Mutagenesis).

In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Valganciclovir should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see Dosage, Handling and Disposal).

Reprotoxicity studies have not been repeated with valganciclovir because of the rapid and extensive conversion to ganciclovir. Valganciclovir is expected to have similar reprotoxicity effects as ganciclovir. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following i.v. doses of 90 mg/kg/day (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 after daily i.v. doses of >2 mg/kg and daily oral doses of >10 mg/kg. These effects were reversible after daily i.v. doses of 2 mg/kg and daily oral doses of 10 mg/kg, but were irreversible or incompletely reversible after daily i.v. doses of 10 mg/kg and daily oral doses of 100 or 1000 mg/kg. Ganciclovir has also caused hypospermatogenesis in rats after daily oral doses of >100 mg/kg and in dogs after daily i.v. and oral doses of >0.4 mg/kg and 0.2 mg/kg, respectively.

Ganciclovir has been shown to be embryotoxic in rabbits and mice following i.v. administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2× the human exposure based on AUC comparisons), respectively. 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 i.v. doses of 90 mg/kg 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. Valganciclovir tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Note: All dose comparisons presented in this subsection are based on the human AUC following administration of a single 5 mg/kg infusion of i.v. ganciclovir as used during the maintenance phase of treatment. Compared with the single 5 mg/kg i.v. infusion, human exposure is doubled during the i.v. induction phase (5 mg/kg b.i.d). The cross-species dose comparisons should be multiplied by 2 for i.v. induction treatment with i.v. ganciclovir.

Lactation: It is not known whether ganciclovir or valganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely. Mothers should be instructed to discontinue the drug or discontinue nursing if they are receiving valganciclovir tablets.

Precautions

General: Strict adherence to dosage recommendations is essential to avoid overdose. The bioavailability of ganciclovir from tablets is significantly higher than from ganciclovir capsules. Valganciclovir 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 valganciclovir tablets (see Overdose, Symptoms and Treatment and Dosage).

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. If renal function is impaired, dosage adjustments are required for valganciclovir tablets. Such adjustments should be based on measured or estimated creatinine clearance values (see Dosage, Renal Impairment).

For patients on hemodialysis (CrCl <10 mL/min) it is recommended that i.v. ganciclovir be used (in accordance with the dose-reduction algorithm cited in the approved Cytovene Product Monograph section on Dosage, Renal Impairment) rather than valganciclovir tablets (see Dosage, Hemodialysis).

Information to Be Provided to the Patient: 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 been associated with elevations in serum creatinine.

Patients should be instructed to take valganciclovir 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 valganciclovir tablets. Women of childbearing potential should be advised to use effective contraception during treatment with valganciclovir tablets. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with valganciclovir tablets.

Patients should be advised that ganciclovir causes tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

Occupational Hazards: Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of valganciclovir 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 counseled that simultaneous treatment with valganciclovir tablets and zidovudine may not be tolerated by some patients and may result in severe granulocytopenia (neutropenia). Patients should be counseled that concomitant treatment with both ganciclovir and didanosine can cause didanosine serum concentrations to be significantly increased. Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients 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 valganciclovir tablets. Some patients will require more frequent follow-up. 

Drug Interactions: Drug Interaction Studies Conducted with Valganciclovir: Valganciclovir is rapidly and extensively converted to ganciclovir; therefore interactions associated with ganciclovir will be expected for valganciclovir tablets. In a rat in-situ model of intestinal permeability, there was no interaction of valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole and mycophenolate mofetil with valganciclovir.

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.

Didanosine: At an oral dose of 1000 mg ganciclovir every 8 hours and didanosine 200 mg every 12 hours, the steady-state didanosine AUC_0-12 increased approximately 80% when didanosine was administered either 2 hours prior to, or concurrent with, administration of ganciclovir. A decrease in steady-state ganciclovir AUC of 23% was observed when didanosine was administered 2 hours prior to administration of ganciclovir, but ganciclovir AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously. There were no significant changes in renal clearance for either drug.

When the standard i.v. ganciclovir induction dose (5 mg/kg infused over 1 hour every 12 hours) was coadministered with didanosine at a dosage of 200 mg orally every 12 hours, the steady-state didanosine AUC_0-12 increased 70±40% (range: 3 to 121%, n=11) and C_max increased 49±48% (range: −28 to 125%). In a separate study, when the standard i.v. ganciclovir maintenance dosage (5 mg/kg infused over 1 hour every 24 hours) was coadministered with didanosine at a dosage of 200 mg orally every 12 hours, didanosine AUC_0-12 increased 50±26% (range: 22 to 110%, n=11) and C_max increased 36±36% (range: −27 to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC_12-24) were unchanged during the dosing intervals when ganciclovir was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug.

This increase in didanosine plasma concentrations cannot be explained by competition for renal tubular secretion, as there was an increase in the percentage of didanosine dose excreted. This increase could arise from either increased bioavailability or decreased metabolism. However, given the increase in didanosine plasma concentrations in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity.

Didanosine has been associated with pancreatitis. In 3 controlled trials, pancreatitis was reported in 2% of patients taking didanosine and Cytovene (ganciclovir capsules and ganciclovir sodium for injection). The rates of pancreatitis were similar in the i.v. solution and capsule groups.

Other than laboratory abnormalities, concomitant treatment with zidovudine, didanosine, or zalcitabine did not appear to affect the type or frequency of reported adverse events, with the exception of moderately increased rates of diarrhea. Among patients taking Cytovene, as ganciclovir sodium for injection or ganciclovir capsules, the diarrhea rates were 51% and 49% respectively with didanosine versus 39% and 35% respectively without didanosine.

Zidovudine: At a dose of 1000 mg ganciclovir every 8 hours, there was a trend for decreased ganciclovir AUC in the presence of zidovudine 100 mg every 4 hours (18%), but the decrease was not statistically significant. There was a statistically significant increase in AUC for zidovudine (15%) in the presence of ganciclovir.

Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage.

Probenecid: At a dose of 1000 mg ganciclovir every 8 hours, ganciclovir serum concentrations increased 45% in the presence of probenecid 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22%, which is consistent with an interaction involving competition for renal tubular secretion. Patients taking probenecid and valganciclovir should be closely monitored for evidence of ganciclovir toxicity.

Imipenem-cilastatin: Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. These drugs should not be used concomitantly unless the potential benefits outweigh the potential risks.

Zalcitabine: Zalcitabine increased the AUC_0-8 of oral ganciclovir by 13%. There were no statistically significant changes in any of the other pharmacokinetic parameters assessed. Additionally, there were no clinically relevant changes in zalcitabine pharmacokinetics in the presence of oral ganciclovir, although a small increase in the elimination rate constant was observed.

Stavudine: No statistically significant pharmacokinetic interaction was observed when stavudine and oral ganciclovir were given in combination.

Trimethoprim: Trimethoprim statistically significantly decreased the renal clearance of oral ganciclovir by 16.3%, and this was associated with a statistically significant decrease in the terminal elimination rate and corresponding increase in half-life by 15%. However, these changes are unlikely to be clinically significant, as AUC_0-8 and C_max were unaffected. The only statistically significant change in trimethoprim pharmacokinetic parameters when coadministered with ganciclovir was an increase in C_min. However, this is unlikely to be of clinical significance and no dose adjustment is recommended.

Cyclosporine: There was no evidence that introduction of ganciclovir affects the pharmacokinetics of cyclosporine based on the comparison of cyclosporine trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.

Mycophenolate Mofetil: Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (MMF) (1.5 g) and i.v. ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and C_max were 54.3 (±19.0) µg•h/mL and 11.5 (±1.8) µg/mL, respectively, after coadministration of the 2 drugs, compared to 51.0 (±17.0) µg•h/mL and 10.6 (±2.0) µg/mL, respectively, after administration of i.v. ganciclovir alone. The mean (±SD) AUC and C_max of mycophenolic acid (MPA) (n=12) after coadministration were 80.9 (±21.6) µg•h/mL and 27.8 (±13.9) µg/mL, respectively, compared to values of 80.3 (±16.4) µg•h/mL and 30.9 (±11.2) µg/mL, respectively, after administration of mycophenolate mofetil alone. Because phenolic glucuronide of mycophenolic acid (MPAG) plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir are coadministered, patients should be monitored carefully.

Other Medications: It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. In addition, toxicity may be enhanced when ganciclovir is coadministered with other drugs known to be associated with renal impairment. Therefore, drugs known to be myelosuppressive or associated with renal impairment, such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations, other nucleoside analogues, or hydroxyurea, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

Laboratory Testing: Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving valganciclovir tablets (see Adverse Effects), 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/µL at the beginning of treatment. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, it is recommended that treatment with hematopoietic growth factors and/or dose interruption be considered. Increased serum creatinine levels have been observed in trials evaluating valganciclovir tablets. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see Dosage, Renal Impairment).

Mutagenesis / Carcinogenesis: No long-term carcinogenicity studies have been conducted with valganciclovir. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen.

Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo, but did not cause point mutations in bacterial or yeast cells, dominant lethality in mice, or morphologically transformed cells in vitro.

In a study conducted over 18 months, ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1× and 1.4×, respectively, the mean drug exposure in humans following the recommended i.v. dose of 5 mg/kg, based on area under the plasma concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues and liver in females. At the dose of 20 mg/kg/day, 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. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01× the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Children: Safety and efficacy of valganciclovir in children have not been established. The use of valganciclovir in children warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.

Valganciclovir tablets have not been studied in pediatric patients, and the pharmacokinetic characteristics of valganciclovir tablets in this population are not known.

Geriatrics: The pharmacokinetic profiles of valganciclovir 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 valganciclovir (see Dosage).

Clinical studies of valganciclovir 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. Valganciclovir 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 (see Precautions, General and Dosage, Renal Impairment).

Adverse Effects

Experience with Valganciclovir: Valganciclovir is a prodrug of ganciclovir, which is rapidly converted to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir (valganciclovir HCl). All of the adverse events observed in valganciclovir clinical studies have been previously observed with ganciclovir.

The safety profiles of valganciclovir and i.v. ganciclovir during 28 days of randomized study phase (21 days induction dose and 7 days maintenance) in 79 patients each were comparable. The most frequently reported events were diarrhea, neutropenia and pyrexia. More patients reported diarrhea, oral candidiasis, headache and fatigue in the oral valganciclovir arm, and nausea and injection site-related events in the i.v. ganciclovir arm (see Table II).

Table III shows the adverse events regardless of seriousness and drug relationship with an incidence of >5%. This information is based on 2 clinical trials (n=370) where patients with CMV retinitis received valganciclovir at a dosage of 900 mg b.i.d. or q.d., corresponding to the induction or maintenance regimen, respectively. Approximately 50% of these patients received valganciclovir for more than 9 months (maximum duration was 30 months).

The most frequently reported adverse events (% of patients), regardless of seriousness and drug relationship in patients taking valganciclovir reported from these 2 clinical trials (n=370), were diarrhea (38%), pyrexia (26%), nausea (25%), neutropenia (24%) and anemia (22%). The majority of the adverse events were of mild intensity. The most frequently reported adverse reactions (% of patients), regardless of seriousness that were considered related (remotely, possibly or probably) to valganciclovir by the investigator, were neutropenia (21%), anemia (14%), diarrhea (13%) and nausea (9%).

Serious adverse reactions considered related by the company to the use of valganciclovir reported from these two clinical trials (n=370) with a frequency of less than 5% and which are not mentioned in Tables II and III, are listed below:

Hemic and Lymphatic System: leukopenia, pancytopenia, bone marrow depression, aplastic anemia.

Urogenital System: decreased creatinine clearance.

Infections: Events related to bone marrow depression and immune system compromise such as local and systemic infections and sepsis.

Bleeding Complications: potentially life-threatening bleeding associated with thrombocytopenia.

Central and Peripheral Nervous System: convulsion, psychosis, hallucinations, confusion, agitation.

Body as a Whole: valganciclovir hypersensitivity.

Laboratory abnormalities reported with valganciclovir are listed in Table IV.

Experience with Ganciclovir: Valganciclovir is rapidly converted to ganciclovir. Key adverse events reported with ganciclovir, and not mentioned above, are listed below. However, for a full listing of ganciclovir adverse reactions please refer to the current Cytovene product monograph.

GI System Disorders: abdominal distension, cholangitis, dyspepsia, dysphagia, eructation, esophagitis, fecal incontinence, flatulence, gastritis, GI disorder, GI hemorrhage, mouth ulceration, pancreatitis, tongue disorder.

Body as a Whole, General Disorders: ascites, asthenia, bacterial, fungal and viral infections, hemorrhage, malaise, mucous membrane disorder, pain, photosensitivity reaction, rigors, sepsis.

Hepatic System Disorders: hepatitis, jaundice.

Skin and Appendages Disorders: acne, alopecia, dermatitis exfoliative, dry skin, sweating increased, urticaria.

Central and Peripheral Nervous System Disorders: abnormal dreams, amnesia, anxiety, ataxia, coma, dry mouth, emotional disturbance, hyperkinetic syndrome, hypertonia, libido decreased, myoclonic jerks, nervousness, somnolence, thinking abnormal, tremor.

Musculoskeletal System Disorders: musculoskeletal pain, myasthenic syndrome.

Urogenital System Disorders: hematuria present, impotence, renal failure, urinary frequency.

Metabolic and Nutritional Disorders: blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood glucose decreased, blood lactic dehydrogenase increased, blood magnesium decreased, diabetes mellitus, edema, hepatic function abnormal, hypocalcemia, hypokalemia, hypoproteinemia.

Special Senses: amblyopia, blindness, earache, eye hemorrhage, eye pain, deafness, glaucoma, taste disturbance, tinnitus, vision abnormal, vitreous disorder.

Hemic and Lymphatic: eosinophilia, leukocytosis, lymphadenopathy, splenomegaly.

Cardiovascular System Disorders: arrhythmia (including ventricular arrhythmia), hypertension, hypotension, migraine, phlebitis, tachycardia, thrombophlebitis deep, vasodilatation.

Respiratory System Disorders: pleural effusion, sinus congestion.

Postmarketing Experience with Ganciclovir: Adverse reactions from postmarketing spontaneous reports with i.v. and oral ganciclovir not mentioned in any section above, and for which a causal relationship can not be excluded, are listed below. As valganciclovir is rapidly and extensively converted to ganciclovir, such adverse events might also occur with valganciclovir: anaphylaxis, decreased fertility in males.

Adverse events that have been reported during the postmarketing period are consistent with those seen in clinical trials with valganciclovir and ganciclovir. For a full listing of ganciclovir postmarketing adverse events please refer to the current Cytovene product monograph.

Overdose: Symptoms and Treatment

Overdose Experience with Valganciclovir Tablets: One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient’s estimated degree of renal impairment (decreased creatinine clearance).

It is expected that an overdose of valganciclovir tablets could result in increased renal toxicity (see Precautions, General and Dosage, Renal Impairment).

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir tablets. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered.

Overdose Experience with I.V. Ganciclovir: Reports of overdoses with i.v. ganciclovir have been received from clinical trials and during postmarketing experience. In some of these cases no adverse reactions were reported. The majority of patients experienced one or more of the following adverse reactions: Hematological Toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia.

Hepatotoxicity: hepatitis, liver function disorder.

Renal Toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine.

GI Toxicity: abdominal pain, diarrhea, vomiting.

Neurotoxicity: generalized tremor, convulsion.

Dosage

Caution—Strict adherence to dosage recommendations is essential to avoid overdose. Valganciclovir tablets can not be substituted for Cytovene capsules on a one-to-one basis.

Valganciclovir 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 valganciclovir tablets is significantly higher than from ganciclovir capsules. Therefore the dosage and administration of valganciclovir tablets as described below should be closely followed (see Precautions, General, and Overdose: Symptoms and Treatment).

For the Treatment of CMV Retinitis in Patients with Normal Renal Function: Induction Treatment: For patients with active CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) twice a day for 21 days with food. Prolonged induction treatment may increase the risk of bone marrow toxicity (see Warnings, Hematologic).

Maintenance Treatment: Following induction treatment, or in patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) once daily with food. Patients whose retinitis worsens may repeat induction treatment (see Induction Treatment).

Renal Impairment: Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required according to creatinine clearance as shown in Table V (see Precautions, General).

The dose-reduction algorithm was based on predicted ganciclovir exposures. The range of exposures may be greater than in renally sufficient patients. Thus, increased monitoring for cytopenias may be warranted in patients with renal impairment (see Precautions, Laboratory Testing).

*An estimated creatinine clearance can be related to serum creatinine by the following formulas:

For females = 0.85×male value

Hemodialysis: For patients on hemodialysis (CrCl <10 mL/min), it is recommended that i.v. ganciclovir be used (in accordance with the dose-reduction algorithm cited in the approved Cytovene Product Monograph section on Dosage, Renal Impairment) rather than valganciclovir tablets (see Precautions, General).

Patients with Severe Leukopenia, Neutropenia, Anemia, Thrombocytopenia and/or Pancytopenia: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with valganciclovir tablets (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/µL, or the hemoglobin is less than 80 g/L, or the platelet count is less than 25 000/µL (see Warnings, Hematologic, Precautions, Laboratory Testing, and Adverse Effects).

Patient Monitoring: Due to the frequency of leukopenia, granulocytopenia (neutropenia), anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia in patients taking valganciclovir 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 cytopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see Renal Impairment).

Reduction of Dose: Dosage reductions in renally impaired patients are required for valganciclovir tablets (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see Adverse Effects). Valganciclovir tablets should not be administered in patients with severe neutropenia (ANC less than 500/µL), severe thrombocytopenia (platelets less than 25 000/µL), or severe anemia (hemoglobin less than 80 g/L).

Handling and Disposal: Caution should be exercised in the handling of 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 (see Warnings, Pregnancy and Reproduction). 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.

Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g., CSHP, 1991). Disposal of valganciclovir should follow provincial, municipal, and local hospital guidelines or requirements.

Supplied

Each pink, convex, oval, film-coated tablet with "VGC" on one side and "450" on the other side contains: valganciclovir HCl 496.3 mg (corresponding to valganciclovir 450 mg). Nonmedicinal ingredients: crospovidone, microcrystalline cellulose, povidone K-30 and stearic acid powder; Opadry Pink film-coat: hydroxypropyl methylcellulose, polyethylene glycol 400/macrogol, polysorbate 80, synthetic red iron oxide and titanium dioxide. Bottles of 60. Store between 15 and 30°C.

New Product 2002

Information for the Patient

You have been prescribed Valcyte (pronounced Val-site) by your doctor. Reading this information can help you learn about Valcyte (valganciclovir hydrochloride) and how to make this medicine work best for you. This brochure does not provide all known information about Valcyte. If you have any questions or concerns about your treatment, please speak with your doctor or pharmacist.

What is Valcyte? Valcyte is a prescription medication that belongs to the family of drugs known as "antivirals".

What is Valcyte used for? How does it work?

• Valcyte is used to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS). Valcyte works by slowing the growth of CMV virus, the virus that causes CMV retinitis. For most people, Valcyte prevents CMV retinitis from progressing (spreading) into healthy cells as quickly as it would without treatment, thereby protecting eyesight from damage due to CMV disease.
• Valcyte does not cure CMV retinitis, and some people may experience progression of retinitis during or following treatment with Valcyte. Therefore, you must follow your doctor’s advice and have your eyes checked regularly.
• Valcyte is a prodrug of ganciclovir. This means it is changed to ganciclovir once it is absorbed into the body. Ganciclovir is the active part of the drug that actually slows the growth of CMV virus.

Who should take Valcyte? Valcyte is recommended for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).

What should you tell your doctor before you start taking Valcyte? Before beginning treatment with Valcyte, make sure your doctor knows if:

• you have ever had a bad reaction to Valcyte or any of the inactive ingredients shown at the end of this leaflet.
• you have ever had a bad reaction to ganciclovir, acyclovir or valacyclovir.
• you are allergic to other medicines, food and dyes.
• you are taking any other medicines (prescription or nonprescription) including herbal or natural products.
• you have any other illnesses/diseases, including a history of liver or kidney disease.
• you are pregnant, plan on becoming pregnant, or are breast-feeding a child.

This information will help your doctor and you decide whether you should use Valcyte and what extra care may need to be taken while you are on the medication. You should always consult your doctor or pharmacist before using other medications while on Valcyte.

When not to take Valcyte:

• Do not take Valcyte or Cytovene if you have ever had a serious reaction to ganciclovir (as Valcyte Tablets or Cytovene Capsules or Cytovene IV). If you are receiving hemodialysis, the use of i.v. ganciclovir (Cytovene IV) rather than Valcyte tablets is recommended.
• Talk to your doctor if you or your partner are pregnant, become pregnant or want to become pregnant while taking Valcyte. Valcyte may cause birth defects in humans and should not be used during pregnancy. If there is any chance that you or your partner could become pregnant, it is very important for you to use effective contraception during and for at least 90 days following treatment with Valcyte. For women this means using barrier protection (condoms) and one additional form of contraception (birth control pills, intrauterine device). For men this means using barrier protection (condoms).

How should Valcyte be taken? Your doctor has prescribed Valcyte after carefully studying your case. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your Valcyte to anyone else.

• To make sure that your therapy is as effective as possible, take your Valcyte exactly as your doctor prescribes it. Do not skip any doses.
• The usual dosage for adults to get active CMV retinitis under control (induction therapy) is two 450 mg tablets twice a day for 21 days.
• The usual dosage for adults to help keep CMV retinitis under control (maintenance therapy) is two 450 mg tablets once a day.
• Take Valcyte with food.
• Valcyte tablets cannot be substituted for Cytovene capsules on a one-to-one basis. You may be taking 2 Valcyte tablets once daily (maintenance treatment) or twice daily (induction treatment) instead of 2 or 4 Cytovene capsules 3 times a day, but you will be getting higher levels of ganciclovir into your bloodstream. Because Valcyte produces higher blood levels of ganciclovir than Cytovene capsules, you should not substitute one for the other. Talk to your doctor, nurse or pharmacist if you are not sure that you have the right medication.
• Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

What to avoid while taking Valcyte? Tell your doctor or pharmacist about all medications that you are taking, including those you buy over the counter and herbal or natural products. Valcyte may change the effect of other medications.

The following drugs may need to have their dose changed when taken with Valcyte: Videx (didanosine, ddI); Retrovir (zidovudine, ZDV, AZT); and Benemid (probenecid).

• Valcyte may cause birth defects in humans and should not be used during pregnancy. If there is any chance that you or your partner could become pregnant, it is very important for you to use effective contraception during and for at least 90 days following treatment with Valcyte. For women this means using barrier protection (condoms) and one additional form of contraception (birth control pills, intrauterine device). For men this means using barrier protection (condoms). Inform your doctor immediately if you are pregnant, or become pregnant.
• Do not take Valcyte if you are breast-feeding. Talk to your doctor if you are breast-feeding your baby. Women who are HIV-positive should not breast-feed because HIV infection can be passed to the baby via the breast milk.

What should you do if you forget a dose of the medication?

• If you forget to take a dose of Valcyte, take it as soon as possible, then just carry on with the regular times you take your medication. If you remember your missed dose close to the time for your next dose, do not take the missed dose.
• Do not let your Valcyte run out. The amount of virus in your blood may increase if your medicine is stopped, even for a short time.
• It may be a good idea to ask your doctor or pharmacist ahead of time what to do about missed doses.

What are the possible unwanted effects of Valcyte? Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Valcyte.

Blood Problems. Valcyte can cause serious blood cell problems. These include reduced numbers of white blood cells (granulocytopenia or neutropenia), reduced numbers of red blood cells (anemia), and reduced numbers of platelets (thrombocytopenia). Your doctor should recommend that you have blood tests done on a regular basis.

Kidney Problems. Valcyte can cause an increase in serum creatinine (an indicator of kidney function). An increase in serum creatinine may indicate abnormal kidney function. Your doctor may have blood tests done on a regular basis to monitor your serum creatinine.

Common Side Effects. Valcyte can cause other side effects. In studies, the most common side effects with Valcyte were diarrhea, neutropenia (low white cell count), nausea, vomiting, fever, headache, and anemia.

Other Side Effects. Convulsions, sedation, dizziness, ataxia (unsteadiness) and/or confusion have also been reported with the use of Valcyte. If they occur, these side effects may affect a person’s ability to drive a car or operate machinery.

Although there is no information from clinical trials in humans, animal studies indicate that Valcyte may cause cancer.

This listing of side effects is not complete. Your doctor or pharmacist can discuss with you a more complete list of side effects with Valcyte.

How should this product be stored?

• Keep out of the reach of children.
• Store in a clean dry area at room temperature (15 to 30°C).
• Keep container tightly closed.
• Do not use medication after the expiry date on the package.

What does Valcyte contain?

• Valcyte is available as a pink 450 mg film-coated oval tablet.
• Each tablet contains 450 mg of the active ingredient, valganciclovir hydrochloride. Tablets also contain additional (nonmedicinal or inactive) ingredients.

These ingredients are: crospovidone, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone K-30, red iron oxide, stearic acid powder, titanium dioxide.

Reminder: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.

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