RoValcyte

Uses

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

RoValcyte is also used to associated treatment for these conditions: Cytomegalovirus (CMV) Infection, Cytomegalovirus Retinitis

How RoValcyte works

RoValcyte is a prodrug of ganciclovir that exists as a mixture of two diastereomers. After administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases. In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to the monophosphate form by viral protein kinase, then it is further phosphorylated via cellular kinases to produce the triphosphate form. This triphosphate form is slowly metabolized intracellularly. The phosphorylation is dependent upon the viral kinase and occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by ganciclovir triphosphate. Ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed.

Dosage

RoValcyte dosage

Standard Dosage: RoValcyte is administered orally, and should be taken with food. RoValcyte is rapidly and extensively converted into the active ingredient ganciclovir. The bioavailability of ganciclovir from RoValcyte is up to 10-fold higher than from oral ganciclovir.The dosage and administration of RoValcyte tablets or powder for oral solution as described below should be closely followed. The ganciclovir systemic exposure following administration of 900 mg RoValcyte powder for oral solution is equivalent to a 900 mg RoValcyte 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 RoValcyte 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 RoValcyte 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

Side Effects

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

Toxicity

It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity.

Interaction

In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for RoValcyte. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of RoValcyte 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.

Food Interaction

• Take with food.

[Moderate] ADJUST DOSING INTERVAL: Food increases the bioavailability of ganciclovir from the prodrug, valganciclovir.

In 16 HIV-positive subjects, the administration of valganciclovir 875 mg once daily with a high-fat meal containing approximately 600 calories resulted in a 30% increase in the steady-state area under the plasma concentration-time curve (AUC) and a 14% increase in the peak plasma concentration (Cmax) of ganciclovir, with no delay in the time to reach peak plasma concentration (Tmax).

The mechanism is unknown.

MANAGEMENT: The manufacturer recommends that valganciclovir be taken with meals.

RoValcyte Drug Interaction

Moderate: mycophenolate mofetil, mycophenolic acid, tacrolimusMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprimUnknown: aspirin, aspirin, meperidine, apixaban, arginine, furosemide, lithium, metoprolol, acetaminophen, acetaminophen, cyanocobalamin, cholecalciferol, phytonadione, cetirizine

RoValcyte Disease Interaction

Major: hematologic toxicities, renal impairmentModerate: hepatic impairment

Volume of Distribution

• 0.703 ± 0.134 L/kg

Elimination Route

RoValcyte is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%.

Half Life

Approximately 4.08 hours. Increased in patients with renal function impairment.

Clearance

• 3.07+/- 0.64 mL/min/kg [IV administration]
• 5.3 L/hr [Patient with creatinine clearance of 70.4 mL/min]

Elimination Route

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

Pregnancy & Breastfeeding use

Pregnancy: The safety of RoValcyte for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. The use of RoValcyte 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 valganciclovir 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 RoValcyte during labor and delivery has not been established.Lactation: Peri- and postnatal development has not been studied with valganciclovir 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 RoValcyte to the nursing mother.

Contraindication

RoValcyte is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any of the excipients.

Special Warning

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

Storage Condition

Store RoValcyte tablets at 20°C to 25°C; excursions are permitted to 15°C to 30°C

Innovators Monograph

You find simplified version here RoValcyte