Valcyte450 mg

Valcyte is an antiviral medicine used against cytomegalovirus (CMV) infection. Its approved and evidence-based uses are classified below by strength of evidence.

Established / FDA-approved uses

• Treatment of CMV retinitis in adults with acquired immunodeficiency syndrome (AIDS) and other immunocompromised patients at risk of vision-threatening CMV eye disease.
• Prevention (prophylaxis) of CMV disease in adult and certain pediatric (4 months to 16 years) kidney, heart, and kidney-pancreas transplant recipients who are at high risk of developing CMV infection after transplantation.

Guideline-supported / commonly extended uses

• Prevention of CMV disease in other solid organ transplant recipients (e.g. liver, lung) at high risk, based on transplant-society guidelines, even where formal product labeling is transplant-type specific.
• Pre-emptive therapy for asymptomatic CMV viremia detected on surveillance testing in transplant recipients, guided by a specialist.

Off-label uses (specialist-directed only)

• Management of CMV disease in hematopoietic stem cell transplant recipients.
• Treatment of certain other CMV end-organ diseases (e.g. CMV colitis, CMV pneumonitis) in immunocompromised patients, under infectious disease specialist supervision.

Valcyte is not effective against, and should not be used for, infections caused by organisms other than CMV and related herpesviruses.

Each film-coated tablet contains Valganciclovir (as valganciclovir hydrochloride) equivalent to 450 mg of valganciclovir base. In some markets Valganciclovir is also supplied as a powder for oral solution, which is reconstituted to provide 50 mg/mL of valganciclovir after mixing with water.

Valcyte is an oral antiviral drug that acts as a prodrug of ganciclovir. After oral administration it is rapidly and almost completely converted to ganciclovir by esterases in the intestinal wall and liver, which markedly improves the oral bioavailability of ganciclovir. Valcyte is used specifically to treat and prevent disease caused by cytomegalovirus (CMV), a herpesvirus that can cause serious infection in people with weakened immune systems, such as those with AIDS or solid organ transplant recipients on immunosuppressive therapy.

Antiviral agent (anti-cytomegalovirus/anti-CMV agent); Valcyte is the L-valyl ester prodrug of ganciclovir.

Mechanism of action

Valganciclovir itself has minimal antiviral activity; it is hydrolyzed to ganciclovir after absorption. Ganciclovir is then phosphorylated intracellularly, first by a CMV-encoded protein kinase (UL97) and then by cellular kinases, to ganciclovir triphosphate. Ganciclovir triphosphate competitively inhibits the binding of deoxyguanosine triphosphate to viral DNA polymerase and is incorporated into viral DNA, resulting in termination or marked slowing of viral DNA elongation, thereby suppressing CMV replication.

Spectrum

Valganciclovir (via ganciclovir) is active against cytomegalovirus and has additional activity against other herpesviruses, including herpes simplex virus types 1 and 2, varicella-zoster virus, Epstein-Barr virus, and human herpesvirus 6, although it is not approved for routine treatment of these infections.

Pharmacokinetics

Oral bioavailability of ganciclovir from Valganciclovir is substantially higher than from oral ganciclovir itself, and is increased further when taken with food. Ganciclovir is widely distributed, undergoes minimal metabolism, and is eliminated primarily unchanged by the kidneys via glomerular filtration and active tubular secretion; renal impairment significantly prolongs its half-life, which is why dose adjustment is required in such patients.

Valcyte tablets should be taken orally with food to maximize absorption. Tablets should be swallowed whole and must not be crushed, split, or chewed, since the drug is a cytotoxic-type compound and direct contact with broken tablet contents should be avoided. If a powder-for-oral-solution formulation is prescribed, it must be reconstituted exactly as directed (see Reconstitution) and measured using the provided oral dosing dispenser, not a household spoon.

Patients, caregivers, and pregnant individuals should avoid direct skin or mucous membrane contact with crushed tablets or reconstituted solution; if contact occurs, the area should be washed thoroughly with soap and water.

Valcyte (via its active moiety ganciclovir) has several clinically significant drug interactions:

• Zidovudine and other myelosuppressive/cytotoxic drugs (e.g. other antivirals, antineoplastics): additive bone marrow suppression; concurrent use may require dose reduction, interruption, or avoidance, with close blood count monitoring.
• Imipenem-cilastatin: concurrent use has been associated with generalized seizures; co-administration should be avoided unless the potential benefit outweighs the risk.
• Mycophenolate mofetil: both drugs are cleared by renal tubular secretion and may competitively increase each other's plasma concentrations, particularly in renal impairment; monitor for toxicity of both agents.
• Probenecid: reduces renal clearance of ganciclovir, increasing its plasma levels and toxicity risk.
• Didanosine: Valcyte increases didanosine plasma concentrations; monitor for didanosine-related toxicity.
• Other nephrotoxic drugs (e.g. cyclosporine, tacrolimus, amphotericin B): may increase the risk of additive renal impairment, which can secondarily raise ganciclovir levels.

Always inform the prescribing physician of all other medicines, including immunosuppressants, being taken before starting Valcyte.

The most commonly reported side effects of Valcyte include:

• Diarrhea, nausea, vomiting, abdominal pain
• Headache, insomnia, peripheral neuropathy, tremor
• Fever (pyrexia), fatigue
• Neutropenia, anemia, and thrombocytopenia (see Precautions and Warnings for full detail on blood-count monitoring)

Less common but serious effects can include severe bone marrow suppression, renal function changes, and central nervous system effects such as confusion or seizures (see Precautions and Warnings). Patients should promptly report unusual bruising or bleeding, signs of infection, or significant mood/mental changes to their physician.

Pregnancy: Valcyte has shown teratogenic and embryotoxic effects in animal studies, and is presumed to carry a risk of fetal harm. It should be used in pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus, and only under specialist medical supervision for serious CMV disease. Women of reproductive potential should use effective contraception during treatment and for at least 30 days after the last dose; men should use effective contraception during treatment and for at least 90 days after the last dose.

Lactation: It is not known whether Valcyte/ganciclovir passes into human breast milk, but excretion into animal milk has been observed. Because of the potential for serious adverse reactions in a nursing infant, breastfeeding is not recommended during treatment with Valcyte and for a period after the last dose; a physician should be consulted for individualized guidance.

Hematologic toxicity (boxed warning)

Valcyte can cause severe neutropenia, anemia, thrombocytopenia, and pancytopenia, including bone marrow failure in rare cases. Complete blood counts with differential should be monitored regularly (e.g. more frequently in patients with pre-existing cytopenias or renal impairment) throughout treatment, and the dose should be reduced or treatment interrupted if significant cytopenia develops.

Impaired fertility (boxed warning)

Based on animal data, Valcyte may cause temporary or permanent inhibition of spermatogenesis in men and may suppress fertility in women. Patients should discuss potential effects on fertility with their physician before starting treatment.

Fetal toxicity and carcinogenicity (boxed warning)

Valcyte is presumed to increase the risk of birth defects and has shown carcinogenic potential in animal studies at clinically relevant exposures. Effective contraception is required during treatment and for a defined period afterward for both male and female patients of reproductive potential (see Pregnancy and Lactation).

Renal impairment

Because Valcyte (as ganciclovir) is cleared renally, dose and dosing interval must be adjusted based on creatinine clearance; failure to adjust the dose significantly increases the risk of severe hematologic toxicity.

CNS effects

Seizures, confusion, abnormal thinking, ataxia, and psychiatric disturbances have been reported, particularly in patients with renal impairment or elevated ganciclovir levels. Use with caution in patients with a history of seizures or CNS disorders.

General

Valcyte should be used only for the specific CMV indications for which it is prescribed, at the exact dose and duration advised by the physician. Do not stop, extend, skip doses, or share this medicine with others without medical advice, as inconsistent use can affect efficacy and increase toxicity risk.

Overdose with Valcyte may worsen its known toxicities, particularly severe bone marrow suppression (neutropenia, anemia, thrombocytopenia, pancytopenia) and renal toxicity. There is no specific antidote. Hydration and hemodialysis may help reduce plasma ganciclovir concentrations in overdose. Any suspected overdose is a medical emergency: seek immediate medical attention or contact a poison control center/emergency services right away rather than attempting to manage it at home.

Store Valcyte tablets at room temperature (below 30°C), away from light and moisture. If a reconstituted oral solution is dispensed, store it in a refrigerator (2°C–8°C), do not freeze, shake well before each use, and discard any unused solution after the period stated on the label (commonly 49 days after reconstitution). Keep out of reach of children, and keep tablets/solution away from other household members, especially pregnant women.

Renal impairment

Requires dose/frequency reduction based on creatinine clearance; use in patients on hemodialysis is generally not recommended due to insufficient data on safe dosing (see Precautions and Warnings).

Hepatic impairment

Not formally studied; use with caution and close monitoring.

Elderly

No specific dose adjustment beyond that required for age-related decline in renal function; renal function should be assessed before and during treatment.

Pediatric patients

See Pediatric Uses for approved age range and dosing approach.

For CMV retinitis, Valcyte induction therapy is typically given for 21 days, followed by maintenance therapy for as long as the patient remains at risk (i.e., while significantly immunocompromised), under ongoing specialist review. For prevention of CMV disease after transplantation, treatment is typically continued from shortly after transplant until the day recommended for the specific organ transplanted (commonly around 100 days, or longer for higher-risk kidney transplant recipients), as determined by the transplant physician. Treatment duration should never be shortened or extended without medical advice.

Where Valcyte is supplied as a powder for oral solution, reconstitute only with the diluent/water volume specified on the product label. Add the water in the amount directed, then shake the closed bottle vigorously to wet all the powder, let it stand for a few minutes, and shake vigorously again until the powder is fully dissolved, producing a solution of 50 mg/mL. Use only the calibrated oral dosing dispenser provided with the product to measure each dose; do not use a household teaspoon. After reconstitution, store the solution in a refrigerator and discard any unused portion after the number of days stated on the label (commonly 49 days). Avoid direct skin or mucous-membrane contact with the powder or solution.

Antiviral agents; Anti-cytomegalovirus (anti-CMV) agents; Nucleoside analogue prodrugs

Valganciclovir is an inactive prodrug that is converted to ganciclovir after oral absorption. Ganciclovir is phosphorylated within CMV-infected cells (initially by a virus-encoded kinase) to its active triphosphate form, which inhibits viral DNA polymerase and is incorporated into growing viral DNA chains, terminating or greatly slowing further DNA synthesis. This selectively suppresses replication of CMV and related herpesviruses in infected cells.

C (FDA legacy pregnancy category, historically assigned to Valcyte/ganciclovir)

Valcyte is approved for prevention of CMV disease in pediatric kidney and heart transplant recipients aged 4 months to 16 years who are at high risk of CMV infection, with dosing individualized using a body-surface-area and renal-function based formula determined by the treating specialist. Safety and efficacy for treatment of CMV retinitis in children, and for indications or age groups outside this approved transplant-prophylaxis population, have not been established, and Valcyte should not be used in those settings outside specialist supervision.