Valcyte450 mg

Valcyte 450 mg is indicated for the treatment of cytomegalovirus (CMV) retinitis in adult patients with acquired immunodeficiency syndrome (AIDS). Valcyte 450 mg is indicated for the prevention of CMV disease in adult and pediatric solid organ transplant (SOT) patients who are at risk.

Anti-viral drugs

Valcyte 450 mg is an L-valyl ester (prodrug) of ganciclovir, which after oral administration is 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. Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus.In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir mono-phosphate 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 HSV- and HCMV-infected cells with half-lives of 18 and between 6 and 24 hours respectively after removal of extracellular ganciclovir. As phosphorylation is largely dependent on the viral kinase, the 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. Typical antiviral IC 50 against CMV in vitro is in the range 0.08 μM (0.02 μg/ml) to 14 μM (3.5 μg/ml).The clinical antiviral effect of Valcyte 450 mg has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis (clinical trial WV15376). CMV shedding was decreased from 46% (32/69) of patients at study entry to 7% (4/55) of patients following 4 weeks of Valcyte 450 mg treatment.

Standard Dosage: Valcyte 450 mg is administered orally, and should be taken with food. Valcyte 450 mg is rapidly and extensively converted into the active ingredient ganciclovir. The bioavailability of ganciclovir from Valcyte 450 mg is up to 10-fold higher than from oral ganciclovir.The dosage and administration of Valcyte 450 mg tablets or powder for oral solution as described below should be closely followed. The ganciclovir systemic exposure following administration of 900 mg Valcyte 450 mg powder for oral solution is equivalent to a 900 mg Valcyte 450 mg dose administered as two 450 mg tablets.An oral dosing dispenser with 25 mg graduations up to 500 mg is provided with the powder for oral solution. It is recommended that this dispenser is used to measure and administer the dose. Treatment of cytomegalovirus (CMV) retinitis- Adult patients: Induction treatment of CMV retinitis: For patients with active CMV retinitis, the recommended dose is 900 mg twice a day for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity Maintenance treatment of CMV retinitis: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dose is 900 mg once daily. Patients whose retinitis worsens may repeat induction treatment. The duration of maintenance treatment should be determined on an individual basis. Pediatric patients: The safety and efficacy of Valcyte 450 mg in the treatment of CMV retinitis have not been established in adequate and well-controlled clinical studies in pediatric patients.  Prevention of CMV disease in transplantation- Adult patients: For kidney transplant patients, the recommended dose is 900 mg once daily starting within 10 days post-transplantation and continuing until 200 days post-transplantation. For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg once daily starting within 10 days post-transplantation and continuing until 100 days post-transplantation.Pediatric patients: In pediatric solid organ transplant patients from birth, who are at risk of developing CMV disease, the recommended once daily dose of Valcyte 450 mg is based on body surface area (BSA) and creatinine clearance (ClCr) derived from Schwartz formula (ClCr), and is calculated using the equation below:Pediatric dose (mg)= 7 x BSA x ClCr. If the creatinine clearance exceeds 150 ml/min/1.73 m2, then a maximum value of 150 ml/min/1.73 m2

Standard Dosage: Valcyte 450 mg is administered orally, and should be taken with food. Valcyte 450 mg is rapidly and extensively converted into the active ingredient ganciclovir. The bioavailability of ganciclovir from Valcyte 450 mg is up to 10-fold higher than from oral ganciclovir.The dosage and administration of Valcyte 450 mg tablets or powder for oral solution as described below should be closely followed. The ganciclovir systemic exposure following administration of 900 mg Valcyte 450 mg powder for oral solution is equivalent to a 900 mg Valcyte 450 mg dose administered as two 450 mg tablets.An oral dosing dispenser with 25 mg graduations up to 500 mg is provided with the powder for oral solution. It is recommended that this dispenser is used to measure and administer the dose. Treatment of cytomegalovirus (CMV) retinitis- Adult patients: Induction treatment of CMV retinitis: For patients with active CMV retinitis, the recommended dose is 900 mg twice a day for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity Maintenance treatment of CMV retinitis: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dose is 900 mg once daily. Patients whose retinitis worsens may repeat induction treatment. The duration of maintenance treatment should be determined on an individual basis. Pediatric patients: The safety and efficacy of Valcyte 450 mg in the treatment of CMV retinitis have not been established in adequate and well-controlled clinical studies in pediatric patients.  Prevention of CMV disease in transplantation- Adult patients: For kidney transplant patients, the recommended dose is 900 mg once daily starting within 10 days post-transplantation and continuing until 200 days post-transplantation. For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg once daily starting within 10 days post-transplantation and continuing until 100 days post-transplantation.Pediatric patients: In pediatric solid organ transplant patients from birth, who are at risk of developing CMV disease, the recommended once daily dose of Valcyte 450 mg is based on body surface area (BSA) and creatinine clearance (ClCr) derived from Schwartz formula (ClCr), and is calculated using the equation below:Pediatric dose (mg)= 7 x BSA x ClCr. If the creatinine clearance exceeds 150 ml/min/1.73 m2, then a maximum value of 150 ml/min/1.73 m2

In vivo drug-drug interaction studies were not conducted with Valcyte 450 mg. However, because Valcyte 450 mg is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for Valcyte 450 mg. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of Valcyte 450 mg and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Valcyte 450 mg is contraindicated in patients with known hypersensitivity to Valcyte 450 mg, ganciclovir or to any of the excipients.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic Toxicity  Acute Renal Failure Impairment of Fertility Fetal Toxicity  Mutagenesis and Carcinogenesis

Pregnancy: The safety of Valcyte 450 mg for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. The use of Valcyte 450 mg should be avoided in pregnant women unless the benefit to the mother outweighs the potential risk to the fetus. Reprotoxicity studies have not been repeated with Valcyte 450 mg because of the rapid and extensive conversion to ganciclovir. In animal studies ganciclovir was associated with reproductive toxicity and teratogenicity (see section 3.3.4 Reproductive Toxicity). The safe use of Valcyte 450 mg during labor and delivery has not been established.Lactation: Peri- and postnatal development has not been studied with Valcyte 450 mg or with ganciclovir but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Human data are not available but animal data indicates that ganciclovir is excreted in the milk of lactating rats. Therefore, a decision should be made to discontinue the drug or discontinue nursing taking into consideration the potential benefit of Valcyte 450 mg to the nursing mother.

Store Valcyte 450 mg tablets at 20°C to 25°C; excursions are permitted to 15°C to 30°C

Pediatric Use: A higher risk of hematological cytopenias in neonates and infants warrants careful monitoring of blood counts in these age groups. Monitoring of liver function abnormalities, renal function and gastrointestinal fluid loss is also recommended in pediatric patients.Geriatric Use: Safety and efficacy have not been established in this patient populationRenal Impairment: In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.Hepatic Impairment: Safety and efficacy have not been established in this patient population

Anti-viral drugs

Valcyte 450 mg is an L-valyl ester (prodrug) of ganciclovir, which after oral administration is 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. Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus.In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir mono-phosphate 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 HSV- and HCMV-infected cells with half-lives of 18 and between 6 and 24 hours respectively after removal of extracellular ganciclovir. As phosphorylation is largely dependent on the viral kinase, the 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. Typical antiviral IC 50 against CMV in vitro is in the range 0.08 μM (0.02 μg/ml) to 14 μM (3.5 μg/ml).The clinical antiviral effect of Valcyte 450 mg has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis (clinical trial WV15376). CMV shedding was decreased from 46% (32/69) of patients at study entry to 7% (4/55) of patients following 4 weeks of Valcyte 450 mg treatment.

Pregnancy: The safety of Valcyte 450 mg for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. The use of Valcyte 450 mg should be avoided in pregnant women unless the benefit to the mother outweighs the potential risk to the fetus. Reprotoxicity studies have not been repeated with Valcyte 450 mg because of the rapid and extensive conversion to ganciclovir. In animal studies ganciclovir was associated with reproductive toxicity and teratogenicity (see section 3.3.4 Reproductive Toxicity). The safe use of Valcyte 450 mg during labor and delivery has not been established.Lactation: Peri- and postnatal development has not been studied with Valcyte 450 mg or with ganciclovir but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Human data are not available but animal data indicates that ganciclovir is excreted in the milk of lactating rats. Therefore, a decision should be made to discontinue the drug or discontinue nursing taking into consideration the potential benefit of Valcyte 450 mg to the nursing mother.

Pediatric Use: A higher risk of hematological cytopenias in neonates and infants warrants careful monitoring of blood counts in these age groups. Monitoring of liver function abnormalities, renal function and gastrointestinal fluid loss is also recommended in pediatric patients.Geriatric Use: Safety and efficacy have not been established in this patient populationRenal Impairment: In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.Hepatic Impairment: Safety and efficacy have not been established in this patient population