VALGANCICLOVIR 450 CIPLA

Indications

• Cytomegalovirus retinitis (induction and maintenance treatment in patients with AIDS)
• Prevention of cytomegalovirus disease following solid organ transplantation from a cytomegalovirus positive donor

Dosage

Children: Refer to the BNF for Children for specific pediatric dosing information.

Adults: Initially 900 mg twice daily for 21 days, then maintenance 900 mg daily. For prevention of CMV disease following kidney transplantation, administer 900 mg daily for 100 days, starting within 10 days of transplantation.

Mechanism of action

Valganciclovir, after oral administration, is rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is phosphorylated in CMV-infected cells to its active triphosphate form, which inhibits viral DNA synthesis by incorporating into the viral DNA and preventing further elongation. This action is selective for virus-infected cells, thus limiting effects on uninfected cells.

Pharmacodynamics

Valganciclovir exhibits antiviral activity against cytomegalovirus. It acts as a guanosine analogue, disrupting DNA synthesis when incorporated into the viral genome. This inhibition of viral replication is critical in treating CMV infections, particularly in patients with weakened immune systems.

Pharmacokinetics

Valganciclovir is well absorbed orally, with peak plasma concentrations occurring within 1 to 3 hours post-dose. It undergoes extensive first-pass metabolism, converting to ganciclovir. The half-life of ganciclovir is approximately 4 hours, and it is primarily eliminated by the kidneys. Renal impairment can significantly affect the drug's clearance, necessitating dose adjustments.

Contra-indications

• Abnormally low haemoglobin count
• History of cytopenia
• Known hypersensitivity to valganciclovir, ganciclovir or any excipients

Adverse effects

• Anaemia
• Neutropenia
• Thrombocytopenia
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Headache
• Dizziness
• Severe fatigue
• Eye disorders (including eye pain and inflammation)
• Hepatic dysfunction
• Potentially severe or fatal haematological effects

Interactions

• Increased risk of haematological toxicity when used with mycophenolate
• Caution with other myelosuppressive agents
• May interact with other antiviral medications

Precautions

• Monitor full blood count closely due to risk of severe cytopenia
• Caution in patients with renal impairment
• Use with caution in patients with a history of cytopenia or those receiving radiotherapy
• Handle with care due to teratogenic and carcinogenic potential

Pregnancy

Manufacturer advises avoiding unless potential benefit outweighs risk due to observed teratogenicity in animal studies.

Breast-feeding

Manufacturer advises avoiding as ganciclovir is present in milk in animal studies.

Storage

Reconstituted powder for oral solution should be stored in a refrigerator (2–8°C) for up to 49 days. Avoid inhalation of powder; if contact with skin or mucous membranes occurs, wash thoroughly with soap and water.

Formulations

• Valganciclovir (as Valganciclovir hydrochloride) 450 mg tablets
• Valganciclovir 500 mg powder for solution for infusion

Mechanism of action

Valganciclovir 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. Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54, synthesis by ganciclovir triphosphate.

Pharmacodynamics

Valganciclovir is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases. After this, it (being an analogue of guanosine) gets incorporated into DNA and thus cannot be properly read by DNA polymerase. This results in the termination of the elongation of viral DNA.