Overview of the Chinese package inserts for Vancevir/Valganciclovir

1. Name: Valganciclovir, Valganciclovir, Valcyte

2. Indications:

1. Adult patients

(1)Treatment of cytomegalovirus (CMV) retinitis: Valganciclovir is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).

(2)Prevention of cytomegalovirus (CMV) disease: Valganciclovir tablets are indicated for the prevention of cytomegalovirus disease in high-risk kidney, heart, and kidney-pancreas transplant patients, especially those whose donors are CMV seropositive and recipients are CMV seronegative (D+/R-).

2. Pediatric patients: Valganciclovir can be used to prevent CMV disease in high-risk kidney transplant patients (4 months to 16 years old) and heart transplant patients (1 month to 6 years old).

3. Usage and dosage:

1. Usage and dosage for adult patients: Patients should use valganciclovir tablets instead of valganciclovir oral liquid.

(1)Treatment of CMV retinitis: During induction therapy, the recommended dosage of valganciclovir is 900 mg orally twice daily (i.e. two 450 mg tablets ), taken continuously for 21 days. After induction therapy, or in adult patients with quiescent CMV retinitis, the recommended dose is 900 mg orally once daily (two 450 mg tablets).

(2) Prevention of CMV disease: For adult patients who have received a heart or kidney-pancreas transplant, the recommended dose is 900 mg (two 450 mg tablets taken) once daily, starting 10 days after transplantation and continuing until 100 days after transplantation. For adult patients who have received a kidney transplant, the recommended dose is also 900 mg (two 450 mg tablets) taken orally once daily, starting 10 days after transplantation, but the prophylaxis period is extended to 200 days after transplantation.

2. Usage and dosage for pediatric patients:

(1)Dose calculation: The recommended once-daily dose for pediatric patients is based on body surface area (BSA) and creatinine clearance (CrCl), which is derived from the modified Schwartz formula, that is, pediatric dose (mg) = 7 × BSA × CrCl, and ensures that the maximum dose of 900mg/day is not exceeded, calculated using the following equation:

BSA (m²) = height (cm) × weight (kg) ÷ 3600

CrCl (ml/min/1.73m²) = K × Height (cm) ÷ Serum Cr (mg/dl)

Among them,K values vary according to the age and gender of the child. For example, for babies with low birth weight for gestational age less than 1 year old, the K value is 0.33; for babies under 1 year old with birth weight consistent with gestational age, the K value is 0.45; for babies 4 months to less than 1-2 years old, the K value is 0.45; for boys 2-13 years old and girls 2-16 years old, the K value is 0.55; for boys 13-16 years old, the K value is 0.7

If CrCl>150mL/min/1.73m2, the maximum value of 150mL/mi/1.73m2 should be used in the equation.

(2) Medication plan:

For pediatric kidney transplant patients 4 months to 16 years of age, the recommended once-daily mg dose (7 × BSA × CrCl) for prevention of cytomegalovirus disease should be initiated within 10 days after transplantation and continued until day 200 after transplantation. For pediatric heart transplant patients 1 month to 16 years of age, the recommended once-daily mg dose (7 × BSA × CrCl) for CMV disease prophylaxis should also be initiated within 10 days after transplantation, but the prophylaxis period is shortened to 100 days after transplantation.

3. Dosage for special groups: For adult patients with renal impairment, the dose of valganciclovir needs to be adjusted based on creatinine clearance (CrCl).

(1)For adult patients undergoing hemodialysis (CrCl <10mL/min), doctors are unable to make dosage recommendations for valganciclovir;

(2)For patients with CrCl between 10-24mL/min, give 450mg every 2 days, then maintain 450mg twice a week;

(3)For patients with CrCl between 25-39mL/min, give 450mg once daily, and then maintain 450mg every 2 days;

(4)For patients with CrCl 40-59mL/min, give 450 mg twice daily , then maintain once daily450mg;

(5)For patients with CrCl >60 mL/min, administer 900 mg twice daily, then maintain the dose of 900 mg once daily .

4. Adverse reactions:

Valganciclovir is available in two forms: tablets and oral solution preparations. For adult patients, valganciclovir tablets are often taken, and clinical studies have shown that ≥20% of adults The most common adverse reactions reported by patients for at least one indication were diarrhea, pyrexia, fatigue, nausea, tremor, headache, insomnia, urinary tract infection, and vomiting; laboratory abnormalities reported were neutropenia, anemia, leukopenia, and thrombocytopenia.

For pediatric patients, valganciclovir oral solution or tablets may be taken. In clinical studies, ≥20% of pediatric solid organ transplant recipients reported at least one of the most common adverse reactions for at least one indication: diarrhea, fever, upper respiratory tract infection, urinary tract infection, vomiting and headache; laboratory abnormalities reported were neutropenia and leukopenia.

5. Storage:

Valganciclovir tablets are stored within the temperature range of 20°C to 25°C (68°F to 77°F); excursions allowed within the temperature range of 15°C to 30°C (59°F to 86°F).

Dry powder of valganciclovir oral solution may be stored20°C to 25°C (68°F to 77°F); excursions allowed within the temperature range 15°C to 30°C (59°F to 86°F); store the formulated solution under refrigeration at 2°C to 8°C (36°F to 46°F) for not more than 49 days. Do not freeze.

6. Mechanism of action:

Valganciclovir is an antiviral drug with antiCMV activity. It is the prodrug of ganciclovir and exists as a mixture of two diastereoisomers. Following administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases. In cells infected with cytomegalovirus (CMV), ganciclovir is initially phosphorylated by viral protein kinases to the monophosphate form and then further phosphorylated by cellular kinases to produce the triphosphate form. This triphosphate form is metabolized slowly within cells. Phosphorylation is dependent on viral kinases and occurs preferentially in virus-infected cells.

The antiviral activity of ganciclovir is due to the inhibition of viruses by ganciclovir triphosphateDNA synthesis. Ganciclovir triphosphate is incorporated into the DNA strand, replacing many of the adenosine bases. This results in preventing DNA synthesis as the phosphodiester bridges can take longer to build, destabilizing the chain. Ganciclovir inhibits viral DNA polymerase more efficiently than cellular polymerases, and chain elongation is restored when ganciclovir is removed.

7. Overdose:

Adverse reactions following overdose with valganciclovir, some of which resulted in death, have been reported in clinical trials and post-marketing experience. Most patients experienced one or more of the following adverse events: hematologic toxicity, hepatotoxicity, nephrotoxicity, gastrointestinal toxicity, neurotoxicity. Valganciclovir overdose may lead to increased nephrotoxicity. Because ganciclovir is dialysable, dialysis may be helpful in reducing serum concentrations of valganciclovir in patients who have overdosed. Adequate hydration should be maintained and hematopoietic growth factors should be considered.