Valganciclovir

Valganciclovir is an Antiviral Agent belonging to the Pharmacology class of Guanosine analog.

Valganciclovir is used in the treatment of Congenital cytomegalovirus infection, treatment, continuation from neonatal period Cytomegalovirus disease, mild to moderate, treatment in solid organ transplant recipients Cytomegalovirus, treatment, esophagitis or colitis in patients with HIV Cytomegalovirus, preemptive therapy in hematopoietic cell transplant recipients Cytomegalovirus, primary prophylaxis in HIV-exposed/-infected patients Cytomegalovirus, prophylaxis in solid organ transplant recipients Cytomegalovirus retinitis, treatment.

Valganciclovir is well absorbed from the gastrointestinal tract. Food (high-fat meal) increases absorption with bioavailability of approx 60% and widely get distributed to all tissue including CSF and ocular tissue. Plasma protein binding: 1-2% (ganciclovir). It is rapidly and extensively metabolised in the intestinal wall and liver via hydrolysis by intestinal mucosal cells and hepatocytes into ganciclovir and get excreted via urine (80-90%, mainly as ganciclovir). Elimination half-life: 4.08 hours (ganciclovir).

The common side effects of valganciclovir are Hypersensitivity reactions; haematologic toxicity (e.g. severe leucopenia, neutropenia, anaemia, pancytopenia, bone marrow failure, aplastic anaemia); acute renal failure, temporary or permanent spermatogenesis inhibition, fertility suppression, birth defects, cancer.

Valganciclovir is available in the form of dosage forms as Tablets, Oral Solution.

Valganciclovir is available in India, France, Japan, and the USA.

Valganciclovir is rapidly converted to ganciclovir in the body. Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis.

Valganciclovir is available in the form of Tablets And Oral Solution.

Oral: Administer with meals. The preferred dosage form for pediatric patients is the oral solution; however, valganciclovir tablets may be used as long as the calculated dose is within 10% of the available tablet strength (450 mg). Do not break or crush tablets.

Oral solution: Shake well prior to use. Use provided reusable oral syringe to measure and administer dose; do not use a household teaspoon, tablespoon, or other measuring device to measure dose (overdosage may occur).

Valganciclovir is used in the treatment of Congenital cytomegalovirus infection, treatment, continuation from neonatal period Cytomegalovirus disease, mild to moderate, treatment in solid organ transplant recipients Cytomegalovirus, treatment, esophagitis or colitis in patients with HIV Cytomegalovirus, preemptive therapy in hematopoietic cell transplant recipients Cytomegalovirus, primary prophylaxis in HIV-exposed/-infected patients Cytomegalovirus, prophylaxis in solid organ transplant recipients Cytomegalovirus retinitis, treatment.

Valganciclovir is rapidly converted to ganciclovir in the body. Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis.

Valganciclovir is approved for use in the following clinical indications

Cytomegalovirus, prophylaxis in solid organ transplant recipients:

Prevention of cytomegalovirus (CMV) in high-risk adult patients (donor CMV seropositive/recipient CMV seronegative) undergoing kidney, heart, or kidney/pancreas transplantation.

Prevention of CMV in high-risk pediatric patients undergoing kidney transplant (age 4 months to 16 years) or heart transplant (age 1 month to 16 years).

Cytomegalovirus, treatment, retinitis: Treatment of CMV retinitis in patients with AIDS.

Although not approved there have been certain off labelled uses documented for Valganciclovir which includes:

Cytomegalovirus, mild to moderate, treatment in solid organ transplant recipients; Cytomegalovirus, preemptive therapy in hematopoietic cell transplant recipients; Cytomegalovirus, treatment, esophagitis or colitis in patients with HIV.

Cytomegalovirus, mild to moderate, treatment in solid organ transplant recipients (off-label use): Oral: 900 mg twice daily until symptom resolution and 1 or 2 consecutive weekly undetectable CMV viral load samples are obtained and clinical resolution of disease (minimum treatment course: 2 weeks).

Cytomegalovirus, pre-emptive therapy in hematopoietic cell transplant recipients (off-label use): Oral:

<100 days post-transplant: 900 mg twice daily for 7 days (autologous transplant) or 7 to 14 days (allogenic transplant), then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative (minimum total induction and maintenance treatment is 2 weeks when 14 days of twice daily is used and 3 weeks when a 7-day induction course is used).

>100 days post-transplant: 900 mg twice daily for 7 to 14 days, then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative.

Cytomegalovirus, prophylaxis in solid organ transplant recipients: Oral:

900 mg once daily; duration of prophylaxis is dependent on type of transplant, as well as donor and recipient CMV serostatus. Note: Based on limited data, some centres utilize a lower dose of 450 mg once daily in intermediate-risk (CMV-seropositive [CMV R+] transplant recipients). This dosing strategy has not been studied prospectively and has only been primarily described in renal transplant recipients.

Cytomegalovirus, treatment, esophagitis or colitis in patients with HIV (off-label use): Oral: Treat initially with ganciclovir IV; once patient is able to absorb and tolerate oral therapy, may switch to oral valganciclovir 900 mg twice daily for a total duration of 21 to 42 days, or until signs and symptoms have resolved.

Cytomegalovirus retinitis, treatment: Oral:

Induction: 900 mg twice daily for 14 to 21 days followed by maintenance therapy.

Maintenance: 900 mg once daily; may consider discontinuation of chronic maintenance therapy in patients that have received 3 to 6 months of treatment, have inactive lesions, and CD4 count >100 cells/mm³ for 3 to 6 months in response to antiretroviral therapy. Discontinue only after consultation with an ophthalmologist.

Valganciclovir is available in various dosage strengths as 50 mg/mL, 450 mg.

Valganciclovir is available in the form of Tablets, Oral solution.

Dose Adjustment in Kidney patient.

Dose Adjustment in the Paediatric patient:

Congenital cytomegalovirus (CMV) infection, treatment, continuation from neonatal period: Limited data available: Infants 1 to 6 months: Oral: 16 mg/kg/dose every 12 hours for 6 months.

Dosing based on a pharmacokinetic study of 24 neonates which demonstrated that 16 mg/kg/dose twice daily produced similar serum concentrations to ganciclovir 6 mg/kg IV twice daily with a 6-week recommended duration of therapy based on ganciclovir experience . A longer duration of therapy (6 months) was evaluated in a randomized trial of 96 neonates (GA >32 weeks weighing ≥1.8 kg; PNA at time of therapy initiation <30 days) which compared treatment with 6 weeks of therapy (n=47) to 6 months of therapy (n=49); results demonstrated a modest improvement in long-term hearing and developmental outcomes (evaluated at 12 and 24 months of age) with the longer duration of therapy (6-month course); however, short-term improvement (evaluated at 6 months of age) in hearing was not demonstrated.

Cytomegalovirus (CMV) disease, mild to moderate, treatment in solid organ transplant recipients : Note: Limit CrCl value used in equation below to 150 mL/minute/1.73 m² regardless of CrCl calculated in order to avoid overexposure.

Infants, Children, and Adolescents: Oral: Dosing based on BSA and CrCl calculation using modified Schwartz formula which bases k constant on age*:

Dose (mg) = 7 × BSA × CrCl* administered every 12 hours

Maximum dose: 900 mg/dose.

Continue therapy for ≥2 weeks, until symptoms resolve, and until 1 to 2 weekly CMV viral load samples are undetectable or below a test-specific threshold; may also be used as step-down therapy in patients who initially received IV ganciclovir when clinical and virologic control is adequate.

Cytomegalovirus (CMV), treatment, esophagitis or colitis in patients with HIV: Adolescents: Oral: Treat initially with ganciclovir IV; once patient is able to absorb and tolerate oral therapy, may switch to oral valganciclovir 900 mg twice daily for a total duration of 21 to 42 days, or until signs and symptoms have resolved.

Cytomegalovirus (CMV), preemptive therapy in hematopoietic cell transplant recipients: Limited data available: Note: Valganciclovir should be avoided in patients with CMV gastritis or intestinal graft-versus-host disease (GVHD).

BSA-based dosing : Infants ≥9 months, Children, and Adolescents:

Maintenance (following induction): Oral: Dosing based on BSA and CrCl calculation using modified Schwartz formula which bases k constant on age*:

Dose (mg) = 7 × BSA × CrCl* administered every 12 hours; use a maximum of 150 mL/minute/1.73 m² for CrCl in equation even if calculated value is higher.

Maximum dose: 900 mg/dose.

Dosing based on a retrospective evaluation of 46 patients who received preemptive therapy upon CMV reactivation; patients were screened for CMV DNA twice weekly starting 9 days prior to transplantation; 40 of the 46 patients received initial IV induction therapy with ganciclovir; 22 patients received only ganciclovir and 24 patients received valganciclovir; outcomes were similar between the groups.

Fixed dosing : Children and Adolescents weighing ≥40 kg: Note: Only use in patients with good oral intake.

<100 days post-transplant:

Induction: Oral: 900 mg twice daily for 7 days (autologous transplant) or 7 to 14 days (allogenic transplant).

Maintenance: Oral: 900 mg once daily for 1 to 2 weeks or until the indicator test is negative (minimum total induction and maintenance treatment for autologous transplant is 2 weeks; for allogeneic transplants minimum is 2 weeks when 14 days of twice-daily therapy is used and 3 weeks when a 7-day induction course is used).

>100 days post-transplant:

Induction: Oral: 900 mg twice daily for 7 to 14 days.

Maintenance: Oral: 900 mg once daily for 1 to 2 weeks until the indicator test is negative (minimum treatment course is 2 weeks).

Cytomegalovirus (CMV), primary prophylaxis in HIV-exposed/-infected patients: Limited data available:

Infants ≥4 months, Children, and Adolescents ≤16 years : Oral: Dosing based on BSA and CrCl calculation using modified Schwartz formula which bases k constant on age*:

Dose (mg) = 7 × BSA × CrCl* administered once daily; use a maximum of 150 mL/minute/1.73 m² for CrCl in the equation even if calculated value is higher.

Maximum daily dose: 900 mg/day.

Primary prophylaxis can be considered in in CMV-seropositive patients <6 years of age who have a CD4 percentage <5% or ≥6 years of age who have CD4 cell counts <50 cells/mm³. Discontinuation of primary prophylaxis can be considered when CD4 cell count is >10% in <6 years of age or >100 cells/mm³ for children ≥6 years of age. Secondary prophylaxis may be considered in patients with prior disseminated disease, retinitis, neurologic disease, or GI disease with relapse.

Cytomegalovirus (CMV), prophylaxis in solid organ transplant recipients:

Note: To avoid supratherapeutic exposure, especially in patients with normal renal function and low body weight, the CrCl used in dosage calculations should be capped; most hospitals with pediatric solid organ transplant recipients limit the CrCl used to calculate dosage to a value of 150 mL/minute/1.73 m², regardless of value calculated with the Schwartz equation, to avoid overexposure.

Infants, Children, and Adolescents: Limited data available except for kidney and heart transplants.

Oral: Dosing based on BSA and CrCl calculation using modified Schwartz formula which bases k constant on age*:

Dose (mg) = 7 × BSA × CrCl* administered once daily

Maximum daily dose: 900 mg/day.

Initiate therapy within 10 days after transplant; duration of prophylaxis varies depending on organ(s) transplanted, donor and recipient CMV serostatus, and immunosuppressive regimen; typically continued for 3 to 6 months; may be continued up to 12 months in certain cases.

Cytomegalovirus (CMV) retinitis, treatment (AIDS-related): Adolescents:

Induction (active retinitis): Oral: 900 mg twice daily for 14 to 21 days followed by maintenance therapy. For patients with immediate sight-threatening lesions, concomitant use of intravitreal ganciclovir is required.

Maintenance: Oral: 900 mg once daily; may consider discontinuation of chronic maintenance therapy in patients who have received 3 to 6 months of treatment, have inactive lesions, and CD4 count >100 cells/mm³ for 3 to 6 months in response to antiretroviral therapy. Discontinue only after consultation with an ophthalmologist.

May be taken w/ meals to reduce GI discomfort.

Valganciclovir may be contraindicated in the following:

Hypersensitivity (eg, anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation.

Concerns related to adverse effects:

Acute renal failure: Acute renal failure may occur; ensure adequate hydration and use with caution in patients receiving concomitant nephrotoxic agents.

Blood dyscrasias: Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, and bone marrow failure, including aplastic anaemia have been reported. May occur at any time during treatment and worsen with continued use; cell counts usually begin to recover within 3 to 7 days of treatment discontinuation. Do not use in patients with an absolute neutrophil count <500 cells/mm³, platelet count <25,000/mm³, or haemoglobin <8 g/dL; use with caution in patients with preexisting bone marrow suppression, cytopenias, or in those receiving myelosuppressive drugs/irradiation. Monitor CBC and platelet count at baseline and frequently during therapy, especially in infants and in patients with renal impairment, those with previous drug-induced leukopenia, and those with neutrophil counts <1,000 cells/mm³ at treatment initiation.

Carcinogenic/teratogenic: May cause temporary or permanent inhibition of spermatogenesis and suppression of fertility; has the potential to cause birth defects and cancers in humans.

Valganciclovir is rapidly metabolized to acyclovir. Following administration of valganciclovir, acyclovir is present in breast milk; unchanged valganciclovir has not been detected in breast milk.

Coadministration with a high-fat meal increased AUC by 30%.

Management: Valganciclovir should be taken with meals.

The adverse reactions related to molecule Valganciclovir can be categorized as

• Common Adverse effects:

Hypersensitivity reactions; haematologic toxicity (e.g. severe leucopenia, neutropenia, anaemia, pancytopenia, bone marrow failure, aplastic anaemia); acute renal failure, temporary or permanent spermatogenesis inhibition, fertility suppression, birth defects, cancer.

• Less Common adverse effect:

Nausea, abdominal pain, dyspepsia, flatulence, mouth ulceration, dysgeusia, dysphagia, upper abdominal pain, constipation, vomiting, diarrhoea, abdominal distention, pancreatitis.

• Rare adverse effects:

Pain, fatigue, chills, pyrexia, malaise, asthenia.

The clinically relevant drug interactions of Valganciclovir are briefly summarized here:

• Increased risk of haematological adverse effects with zidovudine.
• Increased serum concentration of didanosine. Increased plasma concentration with probenecid.
• Increased risk of seizures with imipenem-cilastatin.
• Enhanced toxic effects with myelosuppressive drugs or agents affecting renal function (e.g. nucleosides [e.g. didanosine, stavudine, zidovudine], nucleotide analogues [e.g. adefovir, tenofovir], immunosuppressants [e.g. ciclosporin, mycophenolate mofetil, tacrolimus], antineoplastic agents [e.g. doxorubicin, hydroxyurea, vinblastine, vincristine], and anti-infective agents [e.g. amphotericin B, dapsone, flucytosine, pentamidine, trimethoprim/sulfonamides]).

The common side of Valganciclovir include the following

• Hypersensitivity reactions; haematologic toxicity (e.g. severe leucopenia, neutropenia, anaemia, pancytopenia, bone marrow failure, aplastic anaemia);
• Acute renal failure, temporary or permanent spermatogenesis inhibition, fertility suppression, birth defects, cancer.

The use of Valganciclovir should be prudent in the following group of special populations:

Pregnancy Category C

After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, is expected to have reproductive toxicity effects similar to ganciclovir. There are no adequate and well-controlled studies of valganciclovir or ganciclovir use in pregnant women.

In animal studies of ganciclovir, embryo-fetal toxicity and structural malformations occurred. Valganciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, pregnant mice and rabbits received ganciclovir at doses that produced 2x the human exposure (based on AUC comparison). Treated rabbits had increased rates of fetal resorption, fetal growth retardation, embryolethality, maternal toxicity, cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, increased fetal resorptions and embryolethality occurred in the presence of maternal/fetal toxicity.

Daily intravenous doses of approximately 1.7x the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach. Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL

Nursing Mothers

It is not known whether valganciclovir (prodrug) or ganciclovir (active drug) are excreted in human milk. Because valganciclovir caused granulocytopenia, anemia and thrombocytopenia in clinical trials and ganciclovir was mutagenic and carcinogenic in animal studies, serious adverse events may occur from ganciclovir exposure in nursing infants [see Boxed Warning, Warnings and Precautions (5.1, 5.3, 5.4)]. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

Pediatric Use

Valganciclovir for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant pediatric patients 4 months to 16 years of age at risk for developing CMV disease.

Geriatric Use

Studies of Valganciclovir for oral solution or tablets have not been conducted in adults older than 65 years of age. 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, usually starting at the low end of the dosing range, 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 kidneys, 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.

Symptoms:

Abdominal pain, diarrhoea, vomiting, generalised tremor, seizure, myelosuppression (e.g. leucopenia, neutropenia, granulocytopenia, pancytopenia, bone marrow failure), hepatitis, liver function disorder, elevated creatinine, worsening of haematuria in patient with pre-existing renal impairment, acute kidney injury.

Management:

Symptomatic and supportive treatment. Adequate hydration and haemodialysis may be useful in reducing serum concentrations of valganciclovir. May consider the use of haematopoietic growth factors.

Pharmacodynamics:

Valganciclovir, an antiviral drug, is a prodrug of ganciclovir. Ganciclovir competitively inhibits the binding of deoxyguanosine-triphosphate to DNA polymerase, thereby preventing viral DNA synthesis.

Pharmacokinetics:

Absorption: Well absorbed from the gastrointestinal tract. Food (high-fat meal) increases absorption. Bioavailability: Approx 60%. Time to peak plasma concentration: 1-3 hours (ganciclovir).

Distribution: Widely distributed to all tissue including CSF and ocular tissue. Plasma protein binding: 1-2% (ganciclovir).

Metabolism: Rapidly and extensively metabolised in the intestinal wall and liver via hydrolysis by intestinal mucosal cells and hepatocytes into ganciclovir.

Excretion: Via urine (80-90%, mainly as ganciclovir). Elimination half-life: 4.08 hours (ganciclovir).

• https://www.pfizer.com/products/product-detail/altace
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022021s008lbl.pdf
• https://go.drugbank.com/drugs/DB00178